Is COMMD5 p.Ser175Arg (c.525C>A) pathogenic?

COMMD5 p.Ser175Arg (c.525C>A) is classified Uncertain significance in COMMD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: ambiguous (0.4217); Very rare (popmax 0.004%, afr).

How common is COMMD5 p.Ser175Arg (c.525C>A) in the general population?

COMMD5 p.Ser175Arg (c.525C>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about COMMD5 p.Ser175Arg (c.525C>A)?

AlphaMissense predicts ambiguous (score 0.4217) — an in-silico prediction, not a clinical call.

COMMD5 p.Ser175Arg

c.525C>A · VCV4005691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4217	ambiguous
REVEL	0.227	benign-leaning
SaProt	LLR -6.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -3.1
Regional constraint	o/e 0.81	unconstrained · MANE · 671 bp · p 0.0015 · regional, not allelic
Overall
CADD	6.391	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 0.004% African / African-American · 3/74,952 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,613,832 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,984
European (non-Finnish)	0.000424%	236,009

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: COMMD5
Protein: p.Ser175Arg
Coding: c.525C>A
MANE Select: NM_014066
Type: single nucleotide variant
Location: chr8:144850814 (GRCh38)
Gene constraint: LOEUF 1.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.49 · 4 PDB
Residue 175: a β-strand; the comm domain

Full COMMD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD5 p.Ala153Thr Uncertain significance ★ ⚠ same type
COMMD5 p.Arg135Gln Uncertain significance ★ ⚠ same type
COMMD5 p.Arg158Trp Uncertain significance ★ ⚠ same type
COMMD5 p.Arg201Gln Uncertain significance ★ ⚠ same type
COMMD5 p.Arg217Ser Uncertain significance ★ ⚠ same type
COMMD5 p.Arg220His Uncertain significance ★ ⚠ same type
COMMD5 p.Arg65Gln Uncertain significance ★ ⚠ same type
COMMD5 p.Arg70His 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/commd5-p-ser175arg (accessed [today's date]).

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