Is COMMD4 p.Arg122Trp (c.364C>T) pathogenic?

COMMD4 p.Arg122Trp (c.364C>T) is classified Uncertain significance in COMMD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1001); Very rare (popmax 0.00501%, amr).

How common is COMMD4 p.Arg122Trp (c.364C>T) in the general population?

COMMD4 p.Arg122Trp (c.364C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about COMMD4 p.Arg122Trp (c.364C>T)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

COMMD4 p.Arg122Trp

c.364C>T · VCV4655794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP 1.4, phastCons 0.083
Regional constraint	o/e 0.97	unconstrained · MANE · 3,912 bp · p 0.66 · regional, not allelic
Overall
CADD	20.6	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 0.00501% Admixed American · 3/59,924 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00143% 23/1,611,248 alleles · very rare exomes 20/1,459,048 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,975
East Asian	0.00224%	44,628
Remaining individualsnot grpmax-eligible	0.00161%	62,250
European (non-Finnish)	0.00144%	69,397
South Asian	0.0011%	90,890

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: COMMD4
Protein: p.Arg122Trp
Coding: c.364C>T
MANE Select: NM_017828
Type: single nucleotide variant
Location: chr15:75339326 (GRCh38)
Gene constraint: LOEUF 0.982 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 4 PDB
Residue 122: an α-helix

Full COMMD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD4 p.Ala103Thr Uncertain significance ★ ⚠ same type
COMMD4 p.Ala103Val Uncertain significance ★ ⚠ same type
COMMD4 p.Ala132Thr Uncertain significance ★ ⚠ same type
COMMD4 p.Ala163Thr Uncertain significance ★ ⚠ same type
COMMD4 p.Ala191Thr Uncertain significance ★ ⚠ same type
COMMD4 p.Arg108His Uncertain significance ★ ⚠ same type
COMMD4 p.Arg127Gly Uncertain significance ★ same type
COMMD4 p.Arg137Gln 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/commd4-p-arg122trp (accessed [today's date]).

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