Is COMT p.Val158Met (c.472G>A) pathogenic?

COMT p.Val158Met (c.472G>A) is classified Benign in COMT (ClinVar, Multiple submitters, 9 submitters). AlphaMissense: likely benign (0.1213); Common (popmax 51.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with schizophrenia.

What condition is associated with COMT p.Val158Met (c.472G>A)?

COMT p.Val158Met (c.472G>A) is associated with schizophrenia (ClinVar).

What do computational predictors say about COMT p.Val158Met (c.472G>A)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

COMT p.Val158Met

Q: How common is COMT p.Val158Met (c.472G>A) in the general population?

COMT p.Val158Met (c.472G>A) is common (popmax 51.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.472G>A · rs4680 · VCV17591

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 51.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

schizophrenia

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -7.50	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 -0.16	GERP -3.3, phastCons 0.39
Regional constraint	o/e 0.91	unconstrained · MANE · 6,206 bp · p 0.085 · regional, not allelic
Overall
CADD	16.44	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 51.6% European (non-Finnish) · 609,120/1,179,530 alleles

Filtering AF 51.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.5%

Overall 49% 790,010/1,610,688 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	66.4%	2
Finnishnot grpmax-eligible	55%	2
European (non-Finnish)grpmax	51.6%	2
Middle Eastern	50.4%	2
Remaining individualsnot grpmax-eligible	46.4%	2
Ashkenazi Jewishnot grpmax-eligible	45.9%	2
South Asian	44.8%	2
Admixed American	40.7%	2
African / African-American	30.6%	3
East Asian	28.4%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val158Met
Coding: c.472G>A
MANE Select: NM_000754
dbSNP: rs4680
Type: single nucleotide variant
Location: chr22:19963748 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 158: a UniProt-annotated variant site (in allele comt*2; associated with low enzyme activity and thermolability; may increase the tendency to develop high blood pressure and abdominal obesity)

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

Disease context

schizophrenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMT c.1-5T>A Uncertain significance ★ same condition
COMT p.Ala146Gly Uncertain significance ★ ⚠ same condition
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

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-val158met (accessed [today's date]).

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