Is COX5A p.Ser42Phe (c.125C>T) pathogenic?

COX5A p.Ser42Phe (c.125C>T) is classified Uncertain significance in COX5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely pathogenic (0.5907); Ultra-rare (popmax 0.0164%, mid).

How common is COX5A p.Ser42Phe (c.125C>T) in the general population?

COX5A p.Ser42Phe (c.125C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about COX5A p.Ser42Phe (c.125C>T)?

AlphaMissense predicts likely pathogenic (score 0.5907) — an in-silico prediction, not a clinical call.

COX5A p.Ser42Phe

c.125C>T · VCV4005995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5907	likely pathogenic
REVEL	0.497	indeterminate
SaProt	LLR -11.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,084 alleles

Overall 0.000124% 2/1,613,296 alleles · ultra-rare exomes 1/1,461,150 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0011%	91,058

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.Ser42Phe
Coding: c.125C>T
MANE Select: NM_004255
Type: single nucleotide variant
Location: chr15:74929208 (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.Arg94Gln 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-ser42phe (accessed [today's date]).

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