Is COMMD3 p.Gln135Glu (c.403C>G) pathogenic?

COMMD3 p.Gln135Glu (c.403C>G) is classified Uncertain significance in COMMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: likely benign (0.0849); Ultra-rare (popmax 0.0174%, afr).

How common is COMMD3 p.Gln135Glu (c.403C>G) in the general population?

COMMD3 p.Gln135Glu (c.403C>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about COMMD3 p.Gln135Glu (c.403C>G)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

COMMD3 p.Gln135Glu

c.403C>G · VCV3835499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 3,577 bp · p 0.016 · regional, not allelic
Overall
CADD	23.0	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 0.0174% African / African-American · 13/74,876 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000868% 14/1,613,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,760
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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: COMMD3
Protein: p.Gln135Glu
Coding: c.403C>G
MANE Select: NM_012071
Type: single nucleotide variant
Location: chr10:22318705 (GRCh38)
Gene constraint: LOEUF 1.327 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.84 · 3 PDB
Residue 135: the comm domain; a β-strand

Full COMMD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD3-BMI1 p.Glu2Asp Uncertain significance ★ ⚠ same type
COMMD3-BMI1 p.Leu119Pro Uncertain significance ★ same type
COMMD3 p.Arg120Thr Uncertain significance ★ ⚠ same type
COMMD3 p.Gln194Arg Uncertain significance ★ ⚠ same type
COMMD3 p.His142Gln Uncertain significance ★ ⚠ same type
COMMD3 p.Val155Ala Uncertain significance ★ ⚠ same type
COMMD3 p.Val179Leu Uncertain significance ★ ⚠ same type
COMMD3 p.Tyr163His Likely benign ★ 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/commd3-p-gln135glu (accessed [today's date]).

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