Is COMTD1 p.Ala228Glu (c.683C>A) pathogenic?

COMTD1 p.Ala228Glu (c.683C>A) is classified Likely benign in COMTD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.1008); Rare (popmax 0.214%, mid).

How common is COMTD1 p.Ala228Glu (c.683C>A) in the general population?

COMTD1 p.Ala228Glu (c.683C>A) is rare (popmax 0.214%, mid) (gnomAD).

What do computational predictors say about COMTD1 p.Ala228Glu (c.683C>A)?

AlphaMissense predicts likely benign (score 0.1008) — an in-silico prediction, not a clinical call.

COMTD1 p.Ala228Glu

c.683C>A · rs767889816 · VCV2538920

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1008 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1008	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.26	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 -0.6	GERP -3.5
Regional constraint	o/e 1.02	unconstrained · MANE · 1,852 bp · p 0.73 · regional, not allelic
Overall
CADD	0.012	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 0.214% Middle Eastern · 13/6,062 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00254% 41/1,613,518 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	466
African / African-American	0.004%	25,023
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.00186%	53,637
Admixed American	0.00167%	60,034

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: COMTD1
Protein: p.Ala228Glu
Coding: c.683C>A
MANE Select: NM_144589
dbSNP: rs767889816
Type: single nucleotide variant
Location: chr10:75234179 (GRCh38)
Gene constraint: LOEUF 1.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.67 · 1 PDB
Residue 228: an α-helix

Full COMTD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMTD1 p.Ala126Thr Uncertain significance ★ ⚠ same type
COMTD1 p.Ala126Val Uncertain significance ★ ⚠ same type
COMTD1 p.Ala186Thr Uncertain significance ★ ⚠ same type
COMTD1 p.Ala91Gly Uncertain significance ★ ⚠ same type
COMTD1 p.Arg129Leu Uncertain significance ★ ⚠ same type
COMTD1 p.Arg129Pro Uncertain significance ★ ⚠ same type
COMTD1 p.Arg144Trp Uncertain significance ★ ⚠ same type
COMTD1 p.Arg212Lys 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/comtd1-p-ala228glu (accessed [today's date]).

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