Is COMMD9 p.Arg141His (c.422G>A) pathogenic?

COMMD9 p.Arg141His (c.422G>A) is classified Uncertain significance in COMMD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1311); Ultra-rare (popmax 0.012%, afr).

How common is COMMD9 p.Arg141His (c.422G>A) in the general population?

COMMD9 p.Arg141His (c.422G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about COMMD9 p.Arg141His (c.422G>A)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

COMMD9 p.Arg141His

c.422G>A · rs200282879 · VCV2565679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 15 kb · p 0.55 · regional, not allelic
Overall
CADD	32.0	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 0.012% African / African-American · 9/74,900 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00149% 24/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,322
Admixed American	0.00667%	14,999
South Asian	0.0011%	91,090
European (non-Finnish)	0.000848%	117,991

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: COMMD9
Protein: p.Arg141His
Coding: c.422G>A
MANE Select: NM_014186
dbSNP: rs200282879
Type: single nucleotide variant
Location: chr11:36276171 (GRCh38)
Gene constraint: LOEUF 1.513 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.27 · 7 PDB
Residue 141: the comm domain

Full COMMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD9 p.Ala79= Benign ★★ same type
COMMD9 p.Ala57Ser Uncertain significance ★ ⚠ same type
COMMD9 p.Arg110Lys Uncertain significance ★ ⚠ same type
COMMD9 p.Arg122Cys Uncertain significance ★ ⚠ same type
COMMD9 p.Arg187Cys Uncertain significance ★ ⚠ same type
COMMD9 p.Arg66Cys Uncertain significance ★ ⚠ same type
COMMD9 p.Arg74Cys Uncertain significance ★ ⚠ same type
COMMD9 p.Asp125Asn 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/commd9-p-arg141his (accessed [today's date]).

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