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Appendix sections
A. Coverage Overview
All reviewed pathways at a glance
The coverage table shows where signal was concentrated, where it stayed in the background, and how complete the reviewed evidence was.
| Pathway | Priority | Priority score | Net pathway score | Lower-support points | Higher-support points | Scored variants | Genes reviewed | Variants reviewed | Contributory genes | Interpreted variants | Strong evidence | Seen, not interpreted | Missing | Suggested markers |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Methylation | Worth checking now | 10.0 | -10.0 | 20.0 | 10.0 | 6 | 8 | 20 | 4 | 6 | 1 | 7 | 3 | Homocysteine, methylmalonic acid, folate |
| Glucose | Worth checking now | 9.6 | +2.0 | 5.0 | 7.0 | 6 | 5 | 10 | 4 | 6 | 0 | 0 | 1 | Fasting insulin, fasting glucose, HbA1c |
| Histamine | Worth checking later | 5.8 | -1.0 | 2.0 | 1.0 | 3 | 3 | 8 | 3 | 3 | 0 | 0 | 2 | Plasma histamine, DAO activity, tryptase |
| Lipids | Background only | 2.6 | -1.0 | 1.0 | 0.0 | 1 | 4 | 8 | 1 | 1 | 0 | 0 | 1 | ApoB, triglycerides, LDL-C |
B. Pathway Scorecards
Why each pathway ranked where it did
Methylation
Worth checking now
Overall takeaway: Overall, this pathway may lean toward lower methylation support, but this should be validated with biomarkers.
Direction confidence: High
Net pathway score: -10.0 · 67% lower
Ranked highest because several methylation genes contribute interpretable evidence and the next biomarkers are straightforward to check.
- Lower-support points: 20.0
- Higher-support points: 10.0
- Scored variants: 6
- Genes reviewed: 8
- Variants reviewed: 20
- Main contributors: 1
- Supporting contributors: 3
- Minor contributors: 0
- Not contributing: 4
- Seen, not interpreted: 7
- Missing from file: 3
Glucose
Worth checking now
Overall takeaway: Overall, this pathway shows a mixed pattern, so biomarkers matter more than the genetics alone here.
Direction confidence: High
Net pathway score: +2.0 · 58% higher
Ranks near the top because glucose-related genes line up well enough to justify early lab follow-up.
- Lower-support points: 5.0
- Higher-support points: 7.0
- Scored variants: 6
- Genes reviewed: 5
- Variants reviewed: 10
- Main contributors: 0
- Supporting contributors: 2
- Minor contributors: 2
- Not contributing: 1
- Seen, not interpreted: 0
- Missing from file: 1
Histamine
Worth checking later
Overall takeaway: Overall, this pathway may lean toward slower histamine clearance, but this should be validated with biomarkers.
Direction confidence: Low
Net pathway score: -1.0 · 67% lower
Ranks lower because the signal is lighter and less concentrated than the stronger pathways.
- Lower-support points: 2.0
- Higher-support points: 1.0
- Scored variants: 3
- Genes reviewed: 3
- Variants reviewed: 8
- Main contributors: 0
- Supporting contributors: 0
- Minor contributors: 3
- Not contributing: 0
- Seen, not interpreted: 0
- Missing from file: 2
Lipids
Background only
Overall takeaway: Overall, this pathway may lean toward more strained lipid handling, but this should be validated with biomarkers.
Direction confidence: Low
Net pathway score: -1.0 · 100% lower
Remains in the background because contributory evidence is limited and less coherent than the higher-priority pathways.
- Lower-support points: 1.0
- Higher-support points: 0.0
- Scored variants: 1
- Genes reviewed: 4
- Variants reviewed: 8
- Main contributors: 0
- Supporting contributors: 0
- Minor contributors: 1
- Not contributing: 3
- Seen, not interpreted: 0
- Missing from file: 1
C. Gene Evidence Index
Bridge from pathway ranking to gene-level evidence
This index is the contract between the main report and the deeper evidence layer.
| Gene | Pathway | Role | Contribution score | Net gene score | Lower points | Higher points | Scored variants | Variants reviewed | Interpreted | Strong | Supporting | Seen, not interpreted | Missing | Link |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MTHFR | Methylation | Main contributor | 4.9 | -2.0 | 4.0 | 2.0 | 3 | 4 | 3 | 1 | 1 | 0 | 0 | View gene note |
| SHMT1 | Methylation | Supporting contributor | 2.6 | +2.0 | 0.0 | 2.0 | 1 | 2 | 1 | 0 | 1 | 0 | 1 | View gene note |
| MTRR | Methylation | Supporting contributor | 2.6 | -2.0 | 2.0 | 0.0 | 1 | 3 | 1 | 0 | 1 | 1 | 0 | No gene page yet |
| BHMT | Methylation | Supporting contributor | 2.6 | -2.0 | 2.0 | 0.0 | 1 | 3 | 1 | 0 | 1 | 0 | 0 | View gene note |
| TCN2 | Methylation | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 2 | 0 | View gene note |
| PEMT | Methylation | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 1 | 1 | View gene note |
| COMT | Methylation | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | View gene note |
| CBS | Methylation | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 3 | 0 | 0 | 0 | 2 | 1 | View gene note |
| TCF7L2 | Glucose | Supporting contributor | 2.9 | +3.0 | 0.0 | 3.0 | 2 | 2 | 2 | 0 | 1 | 0 | 0 | View gene note |
| IRS1 | Glucose | Supporting contributor | 2.6 | -2.0 | 2.0 | 0.0 | 2 | 2 | 2 | 0 | 0 | 0 | 0 | View gene note |
| LEPR | Glucose | Minor contributor | 1.3 | +1.0 | 0.0 | 1.0 | 1 | 2 | 1 | 0 | 0 | 0 | 1 | View gene note |
| ADIPOQ | Glucose | Minor contributor | 1.3 | -1.0 | 1.0 | 0.0 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | View gene note |
| FTO | Glucose | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | View gene note |
| HNMT | Histamine | Minor contributor | 1.3 | -1.0 | 1.0 | 0.0 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | View gene note |
| DAO | Histamine | Minor contributor | 1.3 | -1.0 | 1.0 | 0.0 | 1 | 4 | 1 | 0 | 0 | 0 | 1 | View gene note |
| FUT2 | Histamine | Minor contributor | 1.3 | +1.0 | 0.0 | 1.0 | 1 | 2 | 1 | 0 | 0 | 0 | 1 | View gene note |
| ADIPOQ | Lipids | Minor contributor | 1.3 | -1.0 | 1.0 | 0.0 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | View gene note |
| PPARG | Lipids | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | View gene note |
| PPARA | Lipids | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | View gene note |
| APOE | Lipids | Not contributing | 0.0 | 0.0 | 0.0 | 0.0 | 0 | 2 | 0 | 0 | 0 | 0 | 1 | View gene note |
D. Gene Detail Sections
Contributory genes and reviewed variants
MTHFR
Methylation · Main contributor · High
Overall, this gene may lean toward reduced methylation support based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward reduced methylation support based on the reviewed variants.
Medium
May support lower methylation efficiency. This is one of the main genes shaping this pathway in this sample.
Homocysteine, methylmalonic acid, folate
4.9
-2.0
4.0
2.0
3
67% lower
4
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1801131 (A1298C) | GT | Lower support | 3.0 | -3.0 | Strong evidence |
| rs4846051 (MTHFR supporting signal) | AA | Higher support | 2.0 | +2.0 | Supporting evidence |
| rs1801133 (C677T) | AG | Lower support | 1.0 | -1.0 | Weak evidence |
| rs2066470 (MTHFR regulatory signal) | GG | No effect | 0.0 | 0.0 | No clear effect |
SHMT1
Methylation · Supporting contributor · Medium
Overall, this gene may lean toward stronger methylation-related activity based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward stronger methylation-related activity based on the reviewed variants.
Medium
May support stronger methylation-related activity. It adds support to the pathway pattern but does not drive it alone.
Homocysteine, methylmalonic acid, folate
2.6
+2.0
0.0
2.0
1
100% higher
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1979277 (SHMT1 C1420T) | AG | Higher support | 2.0 | +2.0 | Supporting evidence |
| rs9909104 (SHMT1 supporting signal) | Missing from file | Missing | 0.0 | 0.0 | Missing from file |
MTRR
Methylation · Supporting contributor · Medium
Overall, this gene may lean toward reduced methylation support based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward reduced methylation support based on the reviewed variants.
Medium
May support lower methylation efficiency. It adds support to the pathway pattern but does not drive it alone.
Homocysteine, methylmalonic acid, folate
2.6
-2.0
2.0
0.0
1
100% lower
3
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1801394 (A66G) | GG | Lower support | 2.0 | -2.0 | Supporting evidence |
| rs162036 (MTRR supporting signal) | AA | No effect | 0.0 | 0.0 | No clear effect |
| rs1532268 (MTRR supporting signal) | CT | Not scored | 0.0 | 0.0 | Seen, not interpreted |
BHMT
Methylation · Supporting contributor · Medium
Overall, this gene may lean toward reduced methylation support based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward reduced methylation support based on the reviewed variants.
Medium
May support lower methylation efficiency. It adds support to the pathway pattern but does not drive it alone.
Homocysteine, methylmalonic acid, folate
2.6
-2.0
2.0
0.0
1
100% lower
3
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs3733890 (BHMT-742G>A) | AA | Lower support | 2.0 | -2.0 | Supporting evidence |
| rs651852 (BHMT supporting signal) | CC | No effect | 0.0 | 0.0 | No clear effect |
| rs567754 (BHMT supporting signal) | CC | No effect | 0.0 | 0.0 | No clear effect |
TCF7L2
Glucose · Supporting contributor · Medium
Overall, this gene may lean toward more active glucose-related signaling based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward more active glucose-related signaling based on the reviewed variants.
Medium
May support stronger glucose-related activity. It adds support to the pathway pattern but does not drive it alone.
Fasting insulin, fasting glucose, HbA1c
2.9
+3.0
0.0
3.0
2
100% higher
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs7903146 (TCF7L2 primary signal) | TT | Higher support | 2.0 | +2.0 | Supporting evidence |
| rs12255372 (TCF7L2 supporting signal) | GT | Higher support | 1.0 | +1.0 | Weak evidence |
IRS1
Glucose · Supporting contributor · Low
Overall, this gene may lean toward weaker glucose handling based on the reviewed variants. · Medium confidence
Overall, this gene may lean toward weaker glucose handling based on the reviewed variants.
Medium
May make glucose handling harder to regulate. It adds support to the pathway pattern but does not drive it alone.
Fasting insulin, fasting glucose, HbA1c
2.6
-2.0
2.0
0.0
2
100% lower
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs2943641 (IRS1 insulin-response signal) | CC | Lower support | 1.0 | -1.0 | Weak evidence |
| rs7578326 (IRS1 supporting signal) | AA | Lower support | 1.0 | -1.0 | Weak evidence |
LEPR
Glucose · Minor contributor · Low
Overall, this gene may lean toward more active glucose-related signaling based on the reviewed variants. · Low confidence
Overall, this gene may lean toward more active glucose-related signaling based on the reviewed variants.
Low
May support stronger glucose-related activity. It adds limited context but does not strongly affect the overall pathway view.
Fasting insulin, fasting glucose, HbA1c
1.3
+1.0
0.0
1.0
1
100% higher
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1137101 (Q223R) | GG | Higher support | 1.0 | +1.0 | Weak evidence |
| rs1137100 (K109R) | Missing from file | Missing | 0.0 | 0.0 | Missing from file |
ADIPOQ
Glucose · Minor contributor · Low
Overall, this gene may lean toward weaker glucose handling based on the reviewed variants. · Low confidence
Overall, this gene may lean toward weaker glucose handling based on the reviewed variants.
Low
May make glucose handling harder to regulate. It adds limited context but does not strongly affect the overall pathway view.
Fasting insulin, fasting glucose, HbA1c
1.3
-1.0
1.0
0.0
1
100% lower
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1501299 (ADIPOQ +276G>T) | GT | Lower support | 1.0 | -1.0 | Weak evidence |
| rs2241766 (ADIPOQ +45T>G) | TT | No effect | 0.0 | 0.0 | No clear effect |
HNMT
Histamine · Minor contributor · Low
Overall, this gene may lean toward slower histamine clearance based on the reviewed variants. · Low confidence
Overall, this gene may lean toward slower histamine clearance based on the reviewed variants.
Low
May support slower histamine clearance. It adds limited context but does not strongly affect the overall pathway view.
Plasma histamine, DAO activity, tryptase
1.3
-1.0
1.0
0.0
1
100% lower
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1050891 (HNMT supporting signal) | AA | Lower support | 1.0 | -1.0 | Weak evidence |
| rs11558538 (Thr105Ile) | CC | No effect | 0.0 | 0.0 | No clear effect |
DAO
Histamine · Minor contributor · Low
Overall, this gene may lean toward slower histamine clearance based on the reviewed variants. · Low confidence
Overall, this gene may lean toward slower histamine clearance based on the reviewed variants.
Low
May support slower histamine clearance. It adds limited context but does not strongly affect the overall pathway view.
Plasma histamine, DAO activity, tryptase
1.3
-1.0
1.0
0.0
1
100% lower
4
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1049793 (DAO supporting signal) | CG | Lower support | 1.0 | -1.0 | Weak evidence |
| rs2052129 (DAO regulatory signal) | GG | No effect | 0.0 | 0.0 | No clear effect |
| rs1049742 (DAO supporting signal) | Missing from file | Missing | 0.0 | 0.0 | Missing from file |
| rs10156191 (DAO supporting signal) | CC | No effect | 0.0 | 0.0 | No clear effect |
FUT2
Histamine · Minor contributor · Low
Overall, this gene may lean toward faster histamine clearance based on the reviewed variants. · Low confidence
Overall, this gene may lean toward faster histamine clearance based on the reviewed variants.
Low
May support faster histamine clearance. It adds limited context but does not strongly affect the overall pathway view.
Plasma histamine, DAO activity, tryptase
1.3
+1.0
0.0
1.0
1
100% higher
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs602662 (FUT2 supporting signal) | AG | Higher support | 1.0 | +1.0 | Weak evidence |
| rs601338 (Secretor-status signal) | Missing from file | Missing | 0.0 | 0.0 | Missing from file |
ADIPOQ
Lipids · Minor contributor · Low
Overall, this gene may lean toward more strained lipid handling based on the reviewed variants. · Low confidence
Overall, this gene may lean toward more strained lipid handling based on the reviewed variants.
Low
May add mild lipid-handling strain. It adds limited context but does not strongly affect the overall pathway view.
ApoB, triglycerides, LDL-C
1.3
-1.0
1.0
0.0
1
100% lower
2
| Variant | Genotype | Direction | Evidence points | Score impact | Confidence |
|---|---|---|---|---|---|
| rs1501299 (ADIPOQ +276G>T) | GT | Lower support | 1.0 | -1.0 | Weak evidence |
| rs2241766 (ADIPOQ +45T>G) | TT | No effect | 0.0 | 0.0 | No clear effect |
E. Reviewed, Not Contributory
Genes reviewed but not driving the ranking
| Gene | Pathway | Why not contributory | Variants reviewed |
|---|---|---|---|
| TCN2 | Methylation | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
| PEMT | Methylation | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
| COMT | Methylation | Reviewed variants did not materially affect pathway ranking in this sample. | 1 |
| CBS | Methylation | Reviewed variants did not materially affect pathway ranking in this sample. | 3 |
| FTO | Glucose | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
| PPARG | Lipids | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
| PPARA | Lipids | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
| APOE | Lipids | Reviewed variants did not materially affect pathway ranking in this sample. | 2 |
F. Seen, Not Interpreted
Variants shown for completeness, not ranking weight
These variants were seen in the reviewed inventory but were either missing from the uploaded file or not reliable enough to interpret confidently.
| Variant | Gene | Pathway | Reason not interpreted | Still shown because |
|---|---|---|---|---|
| rs9909104 (SHMT1 supporting signal) | SHMT1 | Methylation | Missing from file | Coverage transparency |
| rs1532268 (MTRR supporting signal) | MTRR | Methylation | Not enough evidence yet | Completeness |
| rs9606756 (TCN2 supporting signal) | TCN2 | Methylation | Not enough evidence yet | Completeness |
| rs1801198 (C776G) | TCN2 | Methylation | Not enough evidence yet | Completeness |
| rs7946 (V175M) | PEMT | Methylation | Not enough evidence yet | Completeness |
| rs12325817 (PEMT promoter signal) | PEMT | Methylation | Missing from file | Coverage transparency |
| rs4680 (Val158Met) | COMT | Methylation | Not enough evidence yet | Completeness |
| rs2850144 (CBS supporting signal) | CBS | Methylation | Missing from file | Coverage transparency |
| rs234706 (CBS C699T) | CBS | Methylation | Not enough evidence yet | Completeness |
| rs1801181 (CBS supporting signal) | CBS | Methylation | Not enough evidence yet | Completeness |
| rs1137100 (K109R) | LEPR | Glucose | Missing from file | Coverage transparency |
| rs1049742 (DAO supporting signal) | DAO | Histamine | Missing from file | Coverage transparency |
| rs601338 (Secretor-status signal) | FUT2 | Histamine | Missing from file | Coverage transparency |
| rs429358 (APOE defining SNP) | APOE | Lipids | Missing from file | Coverage transparency |
G. Method Note
How the ranking is produced
4
20
46
- Ranking is based on how concentrated, coherent, and interpretable the reviewed evidence is within each pathway.
- Evidence points use a simple weight system: strong = 3, supporting = 2, weak = 1, and unscored rows = 0.
- Net gene and pathway scores are signed summaries: lower-function evidence subtracts points, higher-function evidence adds points.
- Variants that are missing or not reliable enough to interpret are shown for completeness, but they do not carry equal weight to interpreted findings.
- Absence of signal is not proof of normal function. Biomarkers and symptoms determine whether a pathway matters in practice.