Is COMT p.Ile141Val (c.421A>G) pathogenic?

COMT p.Ile141Val (c.421A>G) is classified Likely benign in COMT (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-30). AlphaMissense: likely benign (0.1359); Rare (popmax 0.277%, afr).

How common is COMT p.Ile141Val (c.421A>G) in the general population?

COMT p.Ile141Val (c.421A>G) is rare (popmax 0.277%, afr) (gnomAD).

What do computational predictors say about COMT p.Ile141Val (c.421A>G)?

AlphaMissense predicts likely benign (score 0.1359) — an in-silico prediction, not a clinical call.

COMT p.Ile141Val

c.421A>G · rs150437940 · VCV790229

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1359 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.277%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1359	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.3
Regional constraint	o/e 0.91	unconstrained · MANE · 6,206 bp · p 0.085 · regional, not allelic
Overall
CADD	0.088	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.277% African / African-American · 208/75,034 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.234%

Overall 0.0135% 217/1,612,922 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.277%	361
Remaining individualsnot grpmax-eligible	0.008%	12,499
Admixed American	0.00666%	15,004

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.Ile141Val
Coding: c.421A>G
MANE Select: NM_000754
dbSNP: rs150437940
Type: single nucleotide variant
Location: chr22:19963697 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 141: a β-strand; a binding site

Full COMT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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-ile141val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown