Is COMTD1 p.Ala126Val (c.377C>T) pathogenic?

COMTD1 p.Ala126Val (c.377C>T) is classified Uncertain significance in COMTD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.00611%, afr).

How common is COMTD1 p.Ala126Val (c.377C>T) in the general population?

COMTD1 p.Ala126Val (c.377C>T) is very rare (popmax 0.00611%, afr) (gnomAD).

What do computational predictors say about COMTD1 p.Ala126Val (c.377C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

COMTD1 p.Ala126Val

c.377C>T · rs1007552236 · VCV2475999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00611%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -9.66	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 6.9	GERP 0.91, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,852 bp · p 0.73 · regional, not allelic
Overall
CADD	21.5	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 0.00611% African / African-American · 4/65,418 alleles

Filtering AF 0.00203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.000285% 4/1,401,238 alleles · very rare

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.Ala126Val
Coding: c.377C>T
MANE Select: NM_144589
dbSNP: rs1007552236
Type: single nucleotide variant
Location: chr10:75235130 (GRCh38)
Gene constraint: LOEUF 1.869 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.67 · 1 PDB

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

Similar variants

COMTD1 p.Ala126Thr Uncertain significance ★ ⚠ same residue
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
COMTD1 p.Arg238Ser 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-ala126val (accessed [today's date]).

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