COMT p.Ala168=
c.504G>A · rs746938556 · VCV726010
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0439%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.023 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -8.9 | GERP -3.5 |
| Overall | ||
| CADD | 0.15 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0439%
South Asian · 40/91,086 alleles
Filtering AF
0.0331%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0293%
Overall
0.00688%
111/1,613,988 alleles · ultra-rare
exomes 104/1,461,784 · genomes 7/152,204 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0439% | 2,277 |
| Remaining individualsnot grpmax-eligible | 0.0112% | 8,927 |
| European (non-Finnish) | 0.00517% | 19,345 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,608 |
| East Asian | 0.00223% | 44,892 |
| Admixed American | 0.00167% | 60,014 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- COMT
- Protein
- p.Ala168=
- Coding
- c.504G>A
- MANE Select
- NM_000754
- dbSNP
- rs746938556
- Type
- single nucleotide variant
- Location
- chr22:19964188 (GRCh38)
- Gene constraint
- LOEUF 1.128 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 94.07 · 12 PDB
- Residue 168
- a binding site
Similar variants
- TXNRD2 p.Ala5Val Uncertain significance ★★ same type
- TXNRD2 p.Ala7Gly Uncertain significance ★★ same type
- TXNRD2 p.Ala7Val Uncertain significance ★★ same type
- TXNRD2 p.Arg9Pro Uncertain significance ★★ same type
- TXNRD2 p.Gly10Ala Uncertain significance ★★ same type
- TXNRD2 p.Gly10Val Uncertain significance ★★ same type
- TXNRD2 p.Leu8Val Uncertain significance ★★ same type
- TXNRD2 p.Met1Thr Uncertain significance ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/comt-p-ala168 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown