Is COMMD6 p.Ala50Pro (c.148G>C) pathogenic?

COMMD6 p.Ala50Pro (c.148G>C) is classified Uncertain significance in COMMD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.9206); Ultra-rare (popmax 0.0283%, amr).

How common is COMMD6 p.Ala50Pro (c.148G>C) in the general population?

COMMD6 p.Ala50Pro (c.148G>C) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about COMMD6 p.Ala50Pro (c.148G>C)?

AlphaMissense predicts likely pathogenic (score 0.9206) — an in-silico prediction, not a clinical call.

COMMD6 p.Ala50Pro

c.148G>C · VCV4005697

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9206 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9206	likely pathogenic
REVEL	0.195	benign-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.37, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 11 kb · p 0.033 · regional, not allelic
Overall
CADD	24.0	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 0.0283% Admixed American · 17/59,972 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00105% 17/1,613,440 alleles · ultra-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: COMMD6
Protein: p.Ala50Pro
Coding: c.148G>C
MANE Select: NM_203495
Type: single nucleotide variant
Location: chr13:75530173 (GRCh38)
Gene constraint: LOEUF 1.538 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 85.37 · 3 PDB
Residue 50: the comm domain; a β-strand

Full COMMD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD6 p.Asp33Asn Uncertain significance ★ ⚠ same type
COMMD6 p.Ile82Thr Uncertain significance ★ ⚠ same type
COMMD6 p.Lys57Asn Uncertain significance ★ ⚠ same type
COMMD6 p.Met28Val Uncertain significance ★ ⚠ same type
COMMD6 p.Met46Ile Uncertain significance ★ ⚠ same type
COMMD6 p.Phe61Ser Uncertain significance ★ ⚠ same type
COMMD6 p.Val30Met 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/commd6-p-ala50pro (accessed [today's date]).

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