Is COMT p.Glu252Asp (c.756G>C) pathogenic?

COMT p.Glu252Asp (c.756G>C) is classified Uncertain significance in COMT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely benign (0.1038); Very rare (popmax 0.00133%, afr).

How common is COMT p.Glu252Asp (c.756G>C) in the general population?

COMT p.Glu252Asp (c.756G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about COMT p.Glu252Asp (c.756G>C)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

COMT p.Glu252Asp

c.756G>C · rs1277428084 · VCV2336011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -4.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.85	GERP -3.1
Regional constraint	o/e 0.91	unconstrained · MANE · 6,206 bp · p 0.085 · regional, not allelic
Overall
CADD	1.341	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Overall 0.000124% 2/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	8.47e-05%	1,180,027

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.Glu252Asp
Coding: c.756G>C
MANE Select: NM_001670 · reported on NM_000754
dbSNP: rs1277428084
Type: single nucleotide variant
Location: chr22:19968676 (GRCh38)

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

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-glu252asp (accessed [today's date]).

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