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Primary topic: mitochondrial energy recovery pathway

Mitochondrial Energy and Recovery Pathway: When Fatigue Needs More Than a Generic Explanation

This pathway matters when fatigue and recovery problems feel real but still look too diffuse when everything gets labeled as oxidative stress.

What this pathway does

The pathway supports mitochondrial biogenesis, throughput, and energy efficiency under load, especially when recovery and endurance become the real questions.

Why it matters

It matters because fatigue can reflect weaker mitochondrial throughput even when redox markers alone do not explain the whole picture.

What creates pressure on this pathway

  • reduced mitochondrial throughput under energetic demand
  • less efficient recovery when ATP production and redox buffering overlap

Validation markers to consider

  • lactate / pyruvate context
  • organic acids
  • recovery pattern

Genes and SNPs connected to this pathway

This is about how your cells turn food and oxygen into usable energy.

Study rows support the SNP/gene claim. The pathway connection comes from the curated gene-to-pathway map.

What may run higher

Stress, fasting, illness, or hard exercise may drain you faster.

What may work more slowly

Your cells may make energy less easily, so fatigue or slow recovery may show up.

What to check next

Check fatigue and recovery patterns, CBC, ferritin, thyroid context, fasting glucose, HbA1c, CK, liver enzymes, and training load.

16mapped genes
26mapped SNPs
28SNP/gene claims
26report eligible
SLC22A55 SNPs - 5 claimsShow SNPsOpen gene page
rs1219088861 claims - 2 study rows

transport activity - TT or compound-heterozygous SLC22A5 deficiency context

OCTN2 carnitine transport activity tendency

Strong

rs121908886 T / SLC22A5 c.844C>T / p.Arg282Ter is associated with lower OCTN2 carnitine transport activity and lower systemic carnitine availability in recessive or compound-heterozygous primary carnitine-deficiency contexts.

SLC22A5 rs121908886 T is staged as a primary carnitine-deficiency nonsense allele affecting OCTN2 carnitine transport.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 6416clinical curation - directClinVar maps rs121908886 to SLC22A5 c.844C>T / p.Arg282Ter and classifies the renal carnitine transport defect record as pathogenic, with literature-linked submissions supporting primary carnitine-deficiency context.GeneReviews Primary Carnitine Deficiencyclinical curation - directGeneReviews supports SLC22A5/OCTN2 loss as the cause of primary carnitine deficiency, with low free carnitine on newborn screening and plasma carnitine monitoring as direct biomarker anchors.
rs2020889211 claims - 2 study rows

transport activity - TT

OCTN2 carnitine transport tendency

Strong

rs202088921 TT / SLC22A5 c.136C>T p.Pro46Ser is associated with lower OCTN2 carnitine transport activity tendency.

SLC22A5 rs202088921 T is staged as a recessive primary carnitine-deficiency allele affecting OCTN2 carnitine transport.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000173299clinical curation - directThe checked ClinVar record maps rs202088921 to SLC22A5 c.136C>T / p.Pro46Ser and classifies it as pathogenic for primary carnitine deficiency, with cited functional evidence for reduced OCTN2 membrane delivery and carnitine transport activity.MedlinePlus SLC22A5clinical curation - directMedlinePlus supports SLC22A5 as the OCTN2 transporter required to move carnitine into cells, tying pathogenic SLC22A5 loss to impaired cellular carnitine availability for fatty-acid oxidation support.
rs572622061 claims - 2 study rows

transport activity - AA or compound-heterozygous SLC22A5 deficiency context

OCTN2 carnitine transport activity tendency

Strong

rs57262206 A / SLC22A5 c.-149G>A is associated with lower OCTN2 carnitine transport activity tendency in recessive or compound-heterozygous deficiency contexts.

SLC22A5 rs57262206 A is staged as a recessive primary carnitine-deficiency allele affecting OCTN2 carnitine transport.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000022286clinical curation - directClinVar maps rs57262206 to SLC22A5 c.-149G>A and classifies it as pathogenic for primary carnitine deficiency, with submission text citing reduced OCTN2 protein and carnitine transport activity.PMID 31187905functional assay - directThe checked PubMed-indexed functional report supports SLC22A5 c.-149G>A as reducing OCTN2 protein abundance and carnitine transport activity.
rs725527251 claims - 2 study rows

transport activity - GG or compound-heterozygous SLC22A5 deficiency context

OCTN2 carnitine transport activity tendency

Strong

rs72552725 G / SLC22A5 c.95A>G / p.Asn32Ser is associated with lower OCTN2 carnitine transport activity and lower systemic carnitine availability in recessive or compound-heterozygous primary carnitine-deficiency contexts.

SLC22A5 rs72552725 G is staged as a pathogenic primary carnitine-deficiency allele affecting OCTN2 carnitine transport.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 25355clinical curation - directClinVar maps rs72552725 to SLC22A5 c.95A>G / p.Asn32Ser, classifies it as pathogenic for renal carnitine transport defect, and includes submitter evidence describing markedly impaired carnitine transport activity in homozygous or affected contexts.MedlinePlus SLC22A5clinical curation - directMedlinePlus describes SLC22A5 as the OCTN2 carnitine transporter required for cellular carnitine uptake and renal carnitine reabsorption; pathogenic changes cause systemic primary carnitine deficiency with low carnitine availability.
rs725527321 claims - 2 study rows

transport activity - TT or compound-heterozygous SLC22A5 deficiency context

OCTN2 carnitine transport activity tendency

Strong

rs72552732 T / SLC22A5 c.1319C>T / p.Thr440Met is associated with lower OCTN2 carnitine transport activity and lower systemic carnitine availability in recessive or compound-heterozygous primary carnitine-deficiency contexts.

SLC22A5 rs72552732 T is staged as a primary carnitine-deficiency allele affecting OCTN2 carnitine transport.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 25416clinical curation - directClinVar maps rs72552732 to SLC22A5 c.1319C>T / p.Thr440Met and classifies the variant in primary carnitine deficiency records.GeneReviews Primary Carnitine Deficiencyclinical curation - directGeneReviews supports SLC22A5/OCTN2 loss as the cause of primary carnitine deficiency, with urinary carnitine wasting, low plasma carnitine, reduced intracellular carnitine accumulation, and impaired fatty-acid oxidation support.
SLC25A204 SNPs - 4 claimsShow SNPsOpen gene page
rs13305786211 claims - 2 study rows

transport activity - AA or compound-heterozygous SLC25A20 deficiency context

Carnitine-acylcarnitine translocase activity tendency

Strong

rs1330578621 A (forward-genomic; SLC25A20 c.823C>T / p.Arg275Ter transcript context) is associated with lower mitochondrial carnitine-acylcarnitine translocase activity tendency and impaired long-chain acylcarnitine transport in recessive or compound-heterozygous CACT deficiency contexts.

SLC25A20 rs1330578621 A is staged as the forward-genomic recessive CACT deficiency nonsense allele affecting mitochondrial long-chain fatty-acid oxidation support.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 1722350clinical curation - directClinVar maps rs1330578621 to SLC25A20 c.823C>T / p.Arg275Ter, a nonsense variant classified pathogenic/likely pathogenic for carnitine-acylcarnitine translocase deficiency with multiple submitters and no conflicts.GeneReviews Carnitine-Acylcarnitine Translocase Deficiencyclinical curation - directGeneReviews supports SLC25A20/CACT as the inner-mitochondrial-membrane transporter exchanging long-chain acylcarnitines and carnitine, with diagnosis supported by acylcarnitines and reduced CACT activity.
rs289345891 claims - 2 study rows

transport activity - CC or compound-heterozygous SLC25A20 deficiency context

Carnitine-acylcarnitine translocase activity tendency

Strong

rs28934589 C / SLC25A20 c.713A>G p.Gln238Arg is associated with lower mitochondrial carnitine-acylcarnitine translocase activity tendency in recessive or compound-heterozygous deficiency contexts.

SLC25A20 rs28934589 C is staged as a recessive CACT deficiency allele affecting mitochondrial long-chain fatty-acid oxidation support.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 12138clinical curation - directClinVar maps rs28934589 to SLC25A20 c.713A>G / p.Gln238Arg, classifies it as pathogenic, and reports very low carnitine-acylcarnitine translocase activity in homozygous patient fibroblast context.PMCID PMC4375124clinical curation - directThe checked CACT deficiency review supports SLC25A20 carnitine-acylcarnitine translocase loss as a mitochondrial fatty-acid oxidation defect with long-chain acylcarnitine profile consequences.
rs5412087101 claims - 2 study rows

transport activity - CC or compound-heterozygous SLC25A20 deficiency context

Carnitine-acylcarnitine translocase activity tendency

Strong

rs541208710 C (forward-genomic; SLC25A20 c.199-10T>G transcript context) is associated with lower mitochondrial carnitine-acylcarnitine translocase activity tendency in recessive or compound-heterozygous deficiency contexts.

SLC25A20 rs541208710 C is staged as the forward-genomic recessive CACT deficiency splice-region allele affecting mitochondrial long-chain fatty-acid oxidation support.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 12137clinical curation - directClinVar maps rs541208710 to SLC25A20 c.199-10T>G, classifies it as pathogenic with multiple submitters and no conflicts, and notes reverse-transcriptase PCR evidence from patient fibroblasts for abnormal splicing.Frontiers Pediatrics 2020 CACT c.199-10T>G case reviewclinical curation - directThe checked Frontiers Pediatrics case review is specifically about late-onset CACT deficiency with SLC25A20 c.199-10T>G and reports acylcarnitine profiling context for the mitochondrial carnitine-acylcarnitine translocase defect.
rs7569986991 claims - 2 study rows

transport activity - AA or compound-heterozygous SLC25A20 deficiency context

Carnitine-acylcarnitine translocase activity tendency

Strong

rs756998699 A / SLC25A20 c.10C>T / p.Gln4Ter is associated with lower mitochondrial carnitine-acylcarnitine translocase activity tendency and impaired long-chain acylcarnitine transport in recessive or compound-heterozygous CACT deficiency contexts.

SLC25A20 rs756998699 A is staged as a recessive CACT deficiency nonsense allele affecting mitochondrial long-chain fatty-acid oxidation support.

Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 203941clinical curation - directClinVar maps rs756998699 to SLC25A20 c.10C>T / p.Gln4Ter and classifies it as pathogenic/likely pathogenic for carnitine-acylcarnitine translocase deficiency with multiple submitters and no conflicts.GeneReviews Carnitine-Acylcarnitine Translocase Deficiencyclinical curation - directGeneReviews supports SLC25A20/CACT as the inner-mitochondrial-membrane transporter exchanging long-chain acylcarnitines and carnitine, with diagnosis supported by elevated C16/C18 acylcarnitines and reduced CACT activity.
ACADS2 SNPs - 2 claimsShow SNPsOpen gene page
rs17999581 claims - 2 study rows

enzyme activity - A

SCAD activity and C4-acylcarnitine tendency

Moderate

rs1799958 A / ACADS Gly209Ser is associated with lower SCAD activity tendency and higher C4-acylcarnitine tendency.

ACADS rs1799958 A is staged as a reduced short-chain acyl-CoA dehydrogenase function allele with acylcarnitine flux support.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PLOS One 2019 ACADS genotype modelfunctional assay - directThe checked PLOS source names rs1799958G>A / p.G209S and reports genotype-dependent ACADS mRNA/protein decrease with altered acylcarnitine flux in cellular fatty-acid oxidation models.ClinVar VCV000003831clinical curation - close proxyClinVar was checked for rs1799958 / ACADS identity and clinical variant context; it is used as supporting curation rather than primary scoring evidence.
rs18005561 claims - 2 study rows

enzyme activity - T

SCAD activity and C4-acylcarnitine tendency

Moderate

rs1800556 T / ACADS Arg171Trp is associated with lower short-chain acyl-CoA dehydrogenase activity tendency and higher C4-acylcarnitine or ethylmalonic-acid biochemical tendency.

ACADS rs1800556 T is staged as a common reduced-SCAD-function biochemical modifier allele.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
GeneReviews SCADDclinical curation - directThe checked GeneReviews chapter identifies ACADS c.511C>T as one of two common variants that can lead to the SCADD biochemical phenotype and reduce enzymatic activity, while emphasizing absent proven clinical significance.JAMA 2006 SCADD heterogeneity studybiomarker association - directThe checked JAMA study defined SCADD biochemically by repeated elevated C4-carnitine and/or ethylmalonic acid plus ACADS mutation or c.511C>T/c.625G>A variants on both alleles, and tabulated c.511C>T as p.Arg171Trp.
ACAT12 SNPs - 2 claimsShow SNPsOpen gene page
rs1995249071 claims - 2 study rows

enzyme activity - GG or compound-heterozygous ACAT1 deficiency context

Mitochondrial acetoacetyl-CoA thiolase activity tendency

Strong

rs199524907 G / ACAT1 c.473A>G / p.Asn158Ser is associated with lower mitochondrial acetoacetyl-CoA thiolase activity tendency and impaired ketone/isoleucine catabolic handling in recessive or compound-heterozygous beta-ketothiolase deficiency contexts.

ACAT1 rs199524907 G is staged as a recessive beta-ketothiolase deficiency allele affecting mitochondrial acetoacetyl-CoA thiolase activity.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 198030clinical curation - directClinVar maps rs199524907 to ACAT1 c.473A>G / p.Asn158Ser, reports pathogenic/likely pathogenic beta-ketothiolase deficiency classifications, and notes observations in affected individuals plus experimental evidence that the missense change affects ACAT1 function.MedlinePlus beta-ketothiolase deficiencyclinical curation - directMedlinePlus supports ACAT1 as a mitochondrial enzyme needed for isoleucine and ketone processing and states that ACAT1 mutations reduce or eliminate enzyme activity in beta-ketothiolase deficiency.
rs5321905941 claims - 3 study rows

enzyme activity - TT or compound-heterozygous ACAT1 deficiency context

Mitochondrial acetoacetyl-CoA thiolase activity tendency

Strong

rs532190594 T / ACAT1 c.622C>T / p.Arg208Ter is associated with lower mitochondrial acetoacetyl-CoA thiolase activity tendency and impaired ketone/isoleucine catabolic handling in recessive or compound-heterozygous deficiency contexts.

ACAT1 rs532190594 T is staged as a recessive beta-ketothiolase deficiency allele affecting mitochondrial acetoacetyl-CoA thiolase activity.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000689417clinical curation - directClinVar maps rs532190594 to ACAT1 c.622C>T / p.Arg208Ter, classifies it as pathogenic with multiple submitters and no conflicts, and describes a premature stop expected to disrupt or eliminate ACAT1 protein product.MedlinePlus beta-ketothiolase deficiencyclinical curation - directMedlinePlus supports ACAT1 as a mitochondrial enzyme needed for isoleucine and ketone processing and states that ACAT1 mutations reduce or eliminate enzyme activity in beta-ketothiolase deficiency.PMCID PMC12958503clinical curation - directThe checked beta-ketothiolase deficiency cohort/review source lists ACAT1 c.622C>T / p.Arg208Ter as pathogenic and describes deficiency biomarkers including C5OH, C4OH, C5:1 and urine organic acids.
CPT22 SNPs - 2 claimsShow SNPsOpen gene page
rs22292911 claims - 2 study rows

enzyme activity - G

CPT II thermolabile activity tendency

Strong

rs2229291 G / CPT2 Phe352Cys is associated with lower thermolabile CPT II activity tendency under high-temperature stress.

CPT2 rs2229291 G is staged as a context-dependent thermolabile CPT II variant affecting mitochondrial long-chain fatty-acid oxidation under fever or heat stress.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PMCID PMC6328901functional assay - directThe checked heatstroke study identifies rs2229291 as CPT2 c.1055T>G / p.Phe352Cys and summarizes the thermolabile phenotype as suppressing mitochondrial ATP production and beta-oxidation during high fever; heatstroke carriers had lower antithrombin activity and more severe clinical scores.PMID 21277129biomarker association - close proxyThe checked pediatric acute-encephalopathy abstract supports the F352C thermolabile CPT II variant as related to low blood ATP levels and severity during infectious fever, providing close human metabolic support for reduced CPT II energy-production capacity under stress.
rs743152941 claims - 2 study rows

enzyme activity - TT

CPT II activity tendency

Strong

rs74315294 TT / CPT2 Ser113Leu is associated with markedly lower CPT II activity tendency.

CPT2 rs74315294 T is staged as a recessive clinical fatty-acid oxidation enzyme variant.

Likely effectLower enzyme activity signal
Signal sizeLarge signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000009510clinical curation - directThe checked ClinVar record maps rs74315294 to CPT2 c.338C>T / p.Ser113Leu and classifies it as pathogenic/likely pathogenic for myopathic CPT II deficiency, with cited functional evidence for reduced CPT II activity.GeneReviews CPT II deficiencyclinical curation - directGeneReviews supports CPT2 Ser113Leu as the common myopathic CPT II deficiency allele affecting long-chain fatty-acid oxidation in biallelic pathogenic contexts.
ACADM1 SNPs - 1 claimsShow SNPsOpen gene page
rs779312341 claims - 2 study rows

enzyme activity - GG

MCAD activity tendency

Strong

rs77931234 GG / ACADM c.985A>G is associated with markedly lower MCAD activity tendency.

ACADM rs77931234 G is staged as a recessive clinical metabolic enzyme variant.

Likely effectLower enzyme activity signal
Signal sizeLarge signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PMCID PMC3444485functional assay - directThe checked MCAD source supports ACADM c.985A>G / Lys329Glu as a major MCAD deficiency variant with reduced residual enzyme activity in relevant genotypes.GeneReviews MCAD deficiencyclinical curation - directGeneReviews clinical curation supports ACADM c.985A>G / Lys329Glu as the common pathogenic MCAD deficiency allele; staged as a recessive enzyme-activity claim.
ACADVL1 SNPs - 1 claimsShow SNPsOpen gene page
rs1139941671 claims - 2 study rows

enzyme activity - CC

VLCAD activity tendency

Strong

rs113994167 CC / ACADVL c.848T>C p.Val283Ala is associated with lower very-long-chain acyl-CoA dehydrogenase activity tendency.

ACADVL rs113994167 C is staged as a recessive VLCAD deficiency allele affecting mitochondrial very-long-chain fatty-acid oxidation.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000020081clinical curation - directThe checked ClinVar record maps rs113994167 to ACADVL c.848T>C / p.Val283Ala and classifies it as pathogenic for VLCAD deficiency, with cited expression evidence for partial residual VLCAD activity.PMCID PMC9090957functional assay - directThe checked VLCAD source discusses ACADVL Val283Ala as a pathogenic variant with functional evidence for reduced VLCAD enzyme activity, supporting a lower-activity claim.
AMPD11 SNPs - 1 claimsShow SNPsOpen gene page
rs176027291 claims - 2 study rows

enzyme activity - T

AMP deaminase activity tendency

Strong

rs17602729 T / AMPD1 C34T is associated with lower AMP deaminase activity tendency.

AMPD1 rs17602729 T is staged as a reduced AMP deaminase activity allele, strongest for TT / deficiency contexts.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PMID 16021918functional assay - directThe checked PubMed abstract reports that the AMPD1 C34T nonsense mutation decreases AMP-deaminase activity in human heart and notes known decreased skeletal-muscle AMP-deaminase activity.PMCID PMC3029538clinical curation - close proxyThe checked case/source summarizes C34T as the main cause of AMPD deficiency and reports markedly reduced muscle AMPD activity even in heterozygous carriers, with deficiency context strongest in homozygotes.
CPT1A1 SNPs - 1 claimsShow SNPsOpen gene page
rs803567791 claims - 2 study rows

biomarker tendency - T

fatty acid oxidation profile tendency

Strong

rs80356779 T / Leu479 is associated with altered CPT1A fatty-acid oxidation profile tendency.

CPT1A rs80356779 T is staged as an ancestry- and diet-context fatty-acid oxidation profile allele.

Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PMCID PMC4920407biomarker association - directThe checked Greenlander metabolomics source identifies CPT1A rs80356779 P479L and reports broad allele-specific erythrocyte fatty-acid profile changes consistent with altered fatty-acid metabolism.PMCID PMC6208583clinical curation - directThe second checked source supports P479L as a CPT1A fatty-acid oxidation/deficiency-associated Arctic variant; staged with ancestry-context limits.
DLD1 SNPs - 1 claimsShow SNPsOpen gene page
rs1219649901 claims - 3 study rows

biomarker tendency - TT or compound-heterozygous DLD deficiency context

DLD/E3 mitochondrial redox dysfunction tendency

Strong

rs121964990 T / DLD c.685G>T / p.Gly229Cys is associated with pathogenic DLD deficiency and mitochondrial E3 redox dysfunction, including increased ROS-generating activity context, in recessive or compound-heterozygous deficiency contexts.

DLD rs121964990 T is staged as a pathogenic DLD deficiency allele affecting shared E3/lipoamide dehydrogenase redox handling.

Likely effectHigher biomarker tendency
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 11966clinical curation - directClinVar maps rs121964990 to DLD c.685G>T / p.Gly229Cys, classifies it as pathogenic, and includes submitter evidence that experimental studies show this missense change affects DLD function.PMID 21558426functional assay - directThe checked functional assay source evaluates disease-causing LADH/DLD mutants including the Gly194Cys/Gly229Cys numbering context and reports increased ROS-generating activity for Gly194Cys without a significant LADH activity change for that exact mutant.GeneReviews DLD deficiencyclinical curation - directGeneReviews supports DLD deficiency as an autosomal recessive mitochondrial disorder with DLD functioning as the E3 component shared by pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain alpha-ketoacid dehydrogenase complexes.
ETFDH1 SNPs - 1 claimsShow SNPsOpen gene page
rs1219649541 claims - 3 study rows

enzyme activity - AA or compound-heterozygous ETFDH deficiency context

Electron-transfer flavoprotein dehydrogenase activity tendency

Strong

rs121964954 A / ETFDH c.250G>A / p.Ala84Thr is associated with lower electron-transfer flavoprotein dehydrogenase activity tendency and riboflavin-responsive multiple acyl-CoA dehydrogenase disruption in recessive or compound-heterozygous deficiency contexts.

ETFDH rs121964954 A is staged as a recessive MADD allele affecting FAD-dependent mitochondrial electron transfer from acyl-CoA dehydrogenases.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 12028clinical curation - directClinVar maps rs121964954 to ETFDH c.250G>A / p.Ala84Thr, classifies it as pathogenic with multiple submitters and no conflicts, and includes submitter comments citing functional A84T knock-in evidence with reduced ETF:QO protein and riboflavin-dependent acylcarnitine changes.BMC Medical Genomics ETFDH riboflavin case reportclinical curation - directThe checked case literature links ETFDH c.250G>A / p.Ala84Thr to riboflavin-responsive MADD with improvement in muscle and acylcarnitine-related disease context after riboflavin therapy.GeneReviews Multiple Acyl-CoA Dehydrogenase Deficiencyclinical curation - directGeneReviews supports MADD as disruption of electron transfer from acyl-CoA dehydrogenases to the respiratory chain, with ETFDH-related forms producing mixed acylcarnitine and organic-acid abnormalities.
GCDH1 SNPs - 1 claimsShow SNPsOpen gene page
rs1214343671 claims - 2 study rows

enzyme activity - TT or compound-heterozygous GCDH deficiency context

Glutaryl-CoA dehydrogenase activity tendency

Strong

rs121434367 T / GCDH c.1262C>T / p.Ala421Val is associated with lower glutaryl-CoA dehydrogenase activity and higher glutaric-acid, 3-hydroxyglutaric-acid, and glutarylcarnitine burden in recessive or compound-heterozygous glutaric acidemia type 1 contexts.

GCDH rs121434367 T is staged as a pathogenic glutaric acidemia type 1 allele affecting mitochondrial organic-acid handling.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
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ClinVar RCV000002163clinical curation - directClinVar maps GCDH c.1262C>T / p.Ala421Val to glutaric aciduria type 1, classifies it pathogenic, and includes a cited expression-study statement that the A421V mutation showed reduced enzyme activity.GeneReviews Glutaric Acidemia Type 1clinical curation - directGeneReviews supports glutaric acidemia type 1 as autosomal recessive GCDH deficiency affecting lysine, hydroxylysine, and tryptophan catabolism, with glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine biomarkers.
HADHA1 SNPs - 1 claimsShow SNPsOpen gene page
rs1378527691 claims - 2 study rows

enzyme activity - GG

LCHAD activity tendency

Strong

rs137852769 GG, corresponding to HADHA c.1528G>C / p.Glu510Gln in transcript orientation, is associated with markedly lower long-chain 3-hydroxyacyl-CoA dehydrogenase activity tendency.

HADHA rs137852769 G is staged as the forward-genomic recessive LCHAD deficiency allele affecting mitochondrial long-chain fatty-acid oxidation.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 100085clinical curation - directThe checked ClinVar record maps rs137852769 to HADHA c.1528G>C / p.Glu510Gln and classifies it as pathogenic for LCHAD deficiency with cited evidence for reduced or absent LCHAD activity.GeneReviews LCHAD/TFP deficiencyclinical curation - directGeneReviews supports LCHAD deficiency as a mitochondrial long-chain fatty-acid oxidation disorder with characteristic long-chain hydroxyacylcarnitine biomarker abnormalities and HADHA pathogenic-variant causality.
HMGCL1 SNPs - 1 claimsShow SNPsOpen gene page
rs1219649971 claims - 3 study rows

enzyme activity - TT or compound-heterozygous HMGCL deficiency context

HMG-CoA lyase ketogenesis activity tendency

Strong

rs121964997 T (forward-genomic; HMGCL c.122G>A / p.Arg41Gln transcript context) is associated with lower HMG-CoA lyase activity tendency and impaired ketogenesis plus leucine catabolic handling in recessive or compound-heterozygous HMGCL deficiency contexts.

HMGCL rs121964997 T is staged as the forward-genomic recessive HMG-CoA lyase deficiency allele affecting ketone-body synthesis and mitochondrial energy handling.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 11957clinical curation - directClinVar maps rs121964997 to HMGCL c.122G>A / p.Arg41Gln and classifies it as pathogenic for HMG-CoA lyase deficiency, with cited experimental evidence that the missense change affects HMGCL function.Orphanet Journal of Rare Diseases HMGCLD reviewclinical curation - directThe checked HMGCLD review supports HMG-CoA lyase deficiency as an autosomal recessive disorder of ketogenesis and leucine degradation with characteristic organic-acid and acylcarnitine findings.HRSA newborn screening HMG-CoA lyase deficiencyclinical curation - directHRSA newborn-screening material supports HMG-CoA lyase deficiency as a disorder with hypoketotic hypoglycemia and abnormal organic-acid/acylcarnitine profiles relevant to the target phenotype.
NOS31 SNPs - 3 claimsShow SNPsOpen gene page
rs17999833 claims - 9 study rows

enzyme activity - TT

NOS3 enzyme activity

Moderate

rs1799983 TT is associated with reduced NOS3 enzyme activity.

NOS3 rs1799983 is scored as a cautious tendency toward lower endothelial nitric oxide synthase activity for T-containing genotypes, strongest for TT.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs1799983 in NOS3 and annotates the common G and T alleles with the endothelial nitric oxide synthase Glu298Asp protein difference. This record scores the common G/T genotype set for a simplified NOS3 functional tendency.PubMed 17449720functional assay - directJoshi et al. studied human endothelial cells by NOS3 Glu298Asp genotype and found that Asp-variant genotypes had lower nitric oxide metabolite production before and after shear exposure, with altered NOS3 caveolar localization and impaired shear response. This supports a lower NOS3 activity tendency for T-containing genotypes.PubMed 37451608review - directA 2023 systematic review and meta-analysis notes that published studies have reported lower circulating nitric oxide with the NOS3 Glu298Asp polymorphism, while clinical association results vary by ancestry and endpoint. This supports keeping the effect as a cautious enzyme-activity tendency rather than a disease prediction.

enzyme activity - GT

NOS3 enzyme activity

Not used for pathway scoring

rs1799983 GT is associated with reduced NOS3 enzyme activity.

NOS3 rs1799983 is scored as a cautious tendency toward lower endothelial nitric oxide synthase activity for T-containing genotypes, strongest for TT.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportModerate support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs1799983 in NOS3 and annotates the common G and T alleles with the endothelial nitric oxide synthase Glu298Asp protein difference. This record scores the common G/T genotype set for a simplified NOS3 functional tendency.PubMed 17449720functional assay - directJoshi et al. studied human endothelial cells by NOS3 Glu298Asp genotype and found that Asp-variant genotypes had lower nitric oxide metabolite production before and after shear exposure, with altered NOS3 caveolar localization and impaired shear response. This supports a lower NOS3 activity tendency for T-containing genotypes.PubMed 37451608review - directA 2023 systematic review and meta-analysis notes that published studies have reported lower circulating nitric oxide with the NOS3 Glu298Asp polymorphism, while clinical association results vary by ancestry and endpoint. This supports keeping the effect as a cautious enzyme-activity tendency rather than a disease prediction.

enzyme activity - GG

NOS3 enzyme activity

Not used for pathway scoring

rs1799983 GG has no scored directional claim for NOS3 enzyme activity.

NOS3 rs1799983 is scored as a cautious tendency toward lower endothelial nitric oxide synthase activity for T-containing genotypes, strongest for TT.

Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs1799983 in NOS3 and annotates the common G and T alleles with the endothelial nitric oxide synthase Glu298Asp protein difference. This record scores the common G/T genotype set for a simplified NOS3 functional tendency.PubMed 17449720functional assay - directJoshi et al. studied human endothelial cells by NOS3 Glu298Asp genotype and found that Asp-variant genotypes had lower nitric oxide metabolite production before and after shear exposure, with altered NOS3 caveolar localization and impaired shear response. This supports a lower NOS3 activity tendency for T-containing genotypes.PubMed 37451608review - directA 2023 systematic review and meta-analysis notes that published studies have reported lower circulating nitric oxide with the NOS3 Glu298Asp polymorphism, while clinical association results vary by ancestry and endpoint. This supports keeping the effect as a cautious enzyme-activity tendency rather than a disease prediction.
SLC25A131 SNPs - 1 claimsShow SNPsOpen gene page
rs803387201 claims - 2 study rows

transport activity - biallelic or compound-heterozygous SLC25A13 deficiency context

Citrin aspartate-glutamate carrier activity tendency

Strong

rs80338720 del / SLC25A13 c.852_855del / p.Met285fs is associated with lower citrin mitochondrial aspartate-glutamate carrier activity and malate-aspartate shuttle support in recessive or compound-heterozygous deficiency contexts.

SLC25A13 rs80338720 deletion is staged as a recessive citrin deficiency allele affecting mitochondrial aspartate-glutamate exchange.

Likely effectLower transport signal
Signal sizeLarge signal
Evidence supportStrong support
Report useIncluded in pathway scoring
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ClinVar RCV000344746clinical curation - directClinVar maps rs80338720 to SLC25A13 c.852_855del / p.Met285fs, classifies it as pathogenic for citrin deficiency, and describes a frameshift/premature stop expected to disrupt SLC25A13 product.GeneReviews Citrin deficiencyclinical curation - directGeneReviews supports citrin as the mitochondrial aspartate-glutamate carrier in the malate-aspartate NADH shuttle and states that SLC25A13 pathogenic variants cause defective NADH shuttle function with urea-cycle, glucose, galactose, fatty-acid synthesis, and acylcarnitine abnormalities.

Where DNA analysis helps

DNA helps separate mitochondrial energy questions from generic oxidative stress or motivation narratives.

Example interpretation

Mitochondrial follow-up may be useful when throughput and recovery genes add a coherent fatigue pattern beyond redox context alone.

Suggested validation: lactate or organic-acid follow-up.

What to do next

  • use organic-acid and lactate context before assuming mitochondrial dysfunction
  • compare PPARGC1A and UCP2 with oxidative-stress genes to see whether energy production deserves separate attention

Related pages

PPARGC1A

PPARGC1A gene DNA analysis

UCP2

UCP2 gene DNA analysis

Low energy

low energy metabolism causes

Lactate, pyruvate, and mitochondrial load

Lactate, pyruvate, and mitochondrial load DNA follow-up

How accurate are DNA metabolism reports?

how accurate are DNA metabolism reports

Best DNA test for metabolism

best DNA test for metabolism

Get the full report

Use your DNA file to see which pathways may be worth validating first.