Is COMMD2 p.Glu8Ala (c.23A>C) pathogenic?

COMMD2 p.Glu8Ala (c.23A>C) is classified Uncertain significance in COMMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.1301); Ultra-rare (popmax 0.0234%, nfe).

How common is COMMD2 p.Glu8Ala (c.23A>C) in the general population?

COMMD2 p.Glu8Ala (c.23A>C) is ultra-rare (popmax 0.0234%, nfe) (gnomAD).

What do computational predictors say about COMMD2 p.Glu8Ala (c.23A>C)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

COMMD2 p.Glu8Ala

c.23A>C · rs763789500 · VCV2379577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.52 · regional, not allelic
Overall
CADD	22.4	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 0.0234% European (non-Finnish) · 276/1,179,928 alleles

Filtering AF 0.0211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0202%

Overall 0.0175% 283/1,613,816 alleles · ultra-rare exomes 274/1,461,672 · genomes 9/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0234%	4,275
African / African-American	0.004%	24,971
Admixed American	0.00333%	29,990
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	63,998

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: COMMD2
Protein: p.Glu8Ala
Coding: c.23A>C
MANE Select: NM_016094
dbSNP: rs763789500
Type: single nucleotide variant
Location: chr3:149752422 (GRCh38)
Gene constraint: LOEUF 1.611 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.00 · 3 PDB
Residue 8: an α-helix

Full COMMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD2 p.Ala118Val Uncertain significance ★ ⚠ same type
COMMD2 p.Ala136Thr Uncertain significance ★ ⚠ same type
COMMD2 p.Ala170Thr Uncertain significance ★ ⚠ same type
COMMD2 p.Arg130Gln Uncertain significance ★ ⚠ same type
COMMD2 p.Arg196His Uncertain significance ★ same type
COMMD2 p.Arg196Leu Uncertain significance ★ ⚠ same type
COMMD2 p.Arg29Leu Uncertain significance ★ ⚠ same type
COMMD2 p.Arg29Trp 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/commd2-p-glu8ala (accessed [today's date]).

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