Is COMMD4 p.Met154Val (c.460A>G) pathogenic?

COMMD4 p.Met154Val (c.460A>G) is classified Uncertain significance in COMMD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0506); Very rare (popmax 0.00223%, eas).

How common is COMMD4 p.Met154Val (c.460A>G) in the general population?

COMMD4 p.Met154Val (c.460A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COMMD4 p.Met154Val (c.460A>G)?

AlphaMissense predicts likely benign (score 0.0506) — an in-silico prediction, not a clinical call.

COMMD4 p.Met154Val

c.460A>G · VCV4232713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0506	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -4.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.5	GERP -2.1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,912 bp · p 0.66 · regional, not allelic
Overall
CADD	1.155	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000929% 15/1,614,094 alleles · very rare exomes 15/1,461,774 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Admixed American	0.00167%	60,022
European (non-Finnish)	0.0011%	90,768

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.Met154Val
Coding: c.460A>G
MANE Select: NM_017828
Type: single nucleotide variant
Location: chr15:75339779 (GRCh38)
Gene constraint: LOEUF 0.982 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85 · 4 PDB
Residue 154: the comm domain; a β-strand

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.Arg122Trp Uncertain significance ★ ⚠ same type
COMMD4 p.Arg127Gly 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-met154val (accessed [today's date]).

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