Is COX5B p.Arg4Ser (c.12G>C) pathogenic?

COX5B p.Arg4Ser (c.12G>C) is classified Uncertain significance in COX5B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: ambiguous (0.5353); Very rare (popmax 0.0013%, nfe).

How common is COX5B p.Arg4Ser (c.12G>C) in the general population?

COX5B p.Arg4Ser (c.12G>C) is very rare (popmax 0.0013%, nfe) (gnomAD).

What do computational predictors say about COX5B p.Arg4Ser (c.12G>C)?

AlphaMissense predicts ambiguous (score 0.5353) — an in-silico prediction, not a clinical call.

COX5B p.Arg4Ser

c.12G>C · rs562812458 · VCV2334090

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5353 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0013%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5353	ambiguous
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.48	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,018 bp · p 0.55 · regional, not allelic
Overall
CADD	31.0	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 0.0013% European (non-Finnish) · 15/1,149,464 alleles

Filtering AF 0.000784% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000621%

Overall 0.00107% 15/1,403,702 alleles · very 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: COX5B
Protein: p.Arg4Ser
Coding: c.12G>C
MANE Select: NM_001862
dbSNP: rs562812458
Type: single nucleotide variant
Location: chr2:97646098 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 85.75 · 3 PDB

Full COX5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX5B c.278-1G>A Uncertain significance ★ same type
COX5B p.Ala54Val Uncertain significance ★ ⚠ same type
COX5B p.Arg112Gln Uncertain significance ★ ⚠ same type
COX5B p.Arg29Cys Uncertain significance ★ ⚠ same type
COX5B p.Arg7Cys Uncertain significance ★ ⚠ same type
COX5B p.Glu109Lys Uncertain significance ★ ⚠ same type
COX5B p.Gly10Ala Uncertain significance ★ ⚠ same type
COX5B p.Gly10Arg 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/cox5b-p-arg4ser (accessed [today's date]).

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