Is COX5A p.Ser25Cys (c.74C>G) pathogenic?

COX5A p.Ser25Cys (c.74C>G) is classified Likely benign in COX5A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.0851); Rare (popmax 0.412%, nfe).

How common is COX5A p.Ser25Cys (c.74C>G) in the general population?

COX5A p.Ser25Cys (c.74C>G) is rare (popmax 0.412%, nfe) (gnomAD).

What do computational predictors say about COX5A p.Ser25Cys (c.74C>G)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

COX5A p.Ser25Cys

c.74C>G · rs200367305 · VCV783061

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.412%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.069, phastCons 0.43
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	17.3	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 0.412% European (non-Finnish) · 4,064/987,190 alleles

Filtering AF 0.401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.397%

Overall 0.349% 4,299/1,232,312 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.412%	243
Remaining individualsnot grpmax-eligible	0.234%	427
Admixed American	0.127%	789
Finnishnot grpmax-eligible	0.126%	795
Ashkenazi Jewishnot grpmax-eligible	0.0844%	1,184
African / African-American	0.0636%	1,571

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.Ser25Cys
Coding: c.74C>G
MANE Select: NM_004255
dbSNP: rs200367305
Type: single nucleotide variant
Location: chr15:74937941 (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.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.Arg94Gln 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-ser25cys (accessed [today's date]).

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