Is COX5A p.Arg94Gln (c.281G>A) pathogenic?

COX5A p.Arg94Gln (c.281G>A) is classified Uncertain significance in COX5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.2224); Very rare (popmax 0.00223%, eas).

How common is COX5A p.Arg94Gln (c.281G>A) in the general population?

COX5A p.Arg94Gln (c.281G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COX5A p.Arg94Gln (c.281G>A)?

AlphaMissense predicts likely benign (score 0.2224) — an in-silico prediction, not a clinical call.

COX5A p.Arg94Gln

c.281G>A · VCV4655965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2224	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -12.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	27.3	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 0.00223% East Asian · 1/44,876 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,613,722 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
Admixed American	0.00167%	59,952
African / African-American	0.00134%	74,896
European (non-Finnish)	0.00017%	589,943

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: COX5A
Protein: p.Arg94Gln
Coding: c.281G>A
MANE Select: NM_004255
Type: single nucleotide variant
Location: chr15:74926824 (GRCh38)
Gene constraint: LOEUF 0.82 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 3 PDB

Full COX5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX5A p.Ser25Cys Likely benign ★★ same type
COX5A p.Ala13Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala32Asp Uncertain significance ★ ⚠ same type
COX5A p.Ala32Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala54Gly Uncertain significance ★ ⚠ same type
COX5A p.Arg107Ser Uncertain significance ★ ⚠ same type
COX5A p.Arg55Cys Uncertain significance ★ ⚠ same type
COX5A p.Arg98Gln 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/cox5a-p-arg94gln (accessed [today's date]).

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