Is COMMD2 p.Ala136Thr (c.406G>A) pathogenic?

COMMD2 p.Ala136Thr (c.406G>A) is classified Uncertain significance in COMMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.8002); Absent from gnomAD v4.1.

How common is COMMD2 p.Ala136Thr (c.406G>A) in the general population?

COMMD2 p.Ala136Thr (c.406G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COMMD2 p.Ala136Thr (c.406G>A)?

AlphaMissense predicts likely pathogenic (score 0.8002) — an in-silico prediction, not a clinical call.

COMMD2 p.Ala136Thr

c.406G>A · VCV3835498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8002 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8002	likely pathogenic
REVEL	0.291	indeterminate
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.52 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COMMD2
Protein: p.Ala136Thr
Coding: c.406G>A
MANE Select: NM_016094
Type: single nucleotide variant
Location: chr3:149741715 (GRCh38)
Gene constraint: LOEUF 1.611 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.00 · 3 PDB
Residue 136: the comm domain; a β-strand

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.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
COMMD2 p.Asn40Thr 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-ala136thr (accessed [today's date]).

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