Is COX5A p.Asp49His (c.145G>C) pathogenic?

COX5A p.Asp49His (c.145G>C) is classified Uncertain significance in COX5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: ambiguous (0.4834); Ultra-rare (popmax 0.0313%, nfe).

How common is COX5A p.Asp49His (c.145G>C) in the general population?

COX5A p.Asp49His (c.145G>C) is ultra-rare (popmax 0.0313%, nfe) (gnomAD).

What do computational predictors say about COX5A p.Asp49His (c.145G>C)?

AlphaMissense predicts ambiguous (score 0.4834) — an in-silico prediction, not a clinical call.

COX5A p.Asp49His

c.145G>C · rs375830469 · VCV2307385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4834	ambiguous
REVEL	0.403	indeterminate
SaProt	LLR -12.42	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.85, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	29.6	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 0.0313% European (non-Finnish) · 369/1,180,008 alleles

Filtering AF 0.0286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0242% 391/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0313%	3,198
Remaining individualsnot grpmax-eligible	0.0128%	7,811
Finnishnot grpmax-eligible	0.0125%	8,005
African / African-American	0.00801%	12,490

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.Asp49His
Coding: c.145G>C
MANE Select: NM_004255
dbSNP: rs375830469
Type: single nucleotide variant
Location: chr15:74929188 (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-asp49his (accessed [today's date]).

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