Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Common
common (popmax 8.74%, afr) — too common for a highly-penetrant pathogenic allele
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.008 | strongly benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -15 | GERP -3.3 |
| Overall | ||
| CADD | 0.34 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
8.74%
African / African-American · 6,556/75,016 alleles
Filtering AF
8.56%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 8.49%
Overall
0.488%
7,876/1,612,932 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 8.74% | 11 |
| Middle Eastern | 0.742% | 135 |
| Admixed American | 0.723% | 138 |
| Remaining individualsnot grpmax-eligible | 0.678% | 147 |
| European (non-Finnish) | 0.0331% | 3,026 |
| South Asian | 0.0231% | 4,337 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0169% | 5,921 |
| Finnishnot grpmax-eligible | 0.00159% | 62,876 |
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.Ala146=
- Coding
- c.438C>T
- MANE Select
- NM_000754
- dbSNP
- rs8192488
- Type
- single nucleotide variant
- Location
- chr22:19963714 (GRCh38)
- Gene constraint
- LOEUF 1.128 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 94.07 · 12 PDB
- Residue 146
- a UniProt-annotated variant site (in); an α-helix
Similar variants
- COMT p.Ala146Gly Uncertain significance ★ ⚠ same residue
- 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
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-ala146 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown