Is COX7B2 p.Pro75Gln (c.224C>A) pathogenic?

COX7B2 p.Pro75Gln (c.224C>A) is classified Uncertain significance in COX7B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: ambiguous (0.5267); Ultra-rare (popmax 0.013%, nfe).

How common is COX7B2 p.Pro75Gln (c.224C>A) in the general population?

COX7B2 p.Pro75Gln (c.224C>A) is ultra-rare (popmax 0.013%, nfe) (gnomAD).

What do computational predictors say about COX7B2 p.Pro75Gln (c.224C>A)?

AlphaMissense predicts ambiguous (score 0.5267) — an in-silico prediction, not a clinical call.

COX7B2 p.Pro75Gln

c.224C>A · VCV4233045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5267	ambiguous
REVEL	0.298	indeterminate
SaProt	LLR -13.86	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 242 bp · p 0.18 · regional, not allelic
Overall
CADD	24.3	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 0.013% European (non-Finnish) · 153/1,179,930 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0096% 155/1,613,784 alleles · ultra-rare exomes 153/1,461,684 · genomes 2/152,100 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.013%	7,712
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,886

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: COX7B2
Protein: p.Pro75Gln
Coding: c.224C>A
MANE Select: NM_130902
Type: single nucleotide variant
Location: chr4:46734969 (GRCh38)
Gene constraint: LOEUF 1.77 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.69

Full COX7B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX7B2 p.Ala58Val Uncertain significance ★ ⚠ same type
COX7B2 p.Asn8Asp Uncertain significance ★ ⚠ same type
COX7B2 p.Glu64Ala Uncertain significance ★ ⚠ same type
COX7B2 p.Ile15Thr Uncertain significance ★ ⚠ same type
COX7B2 p.Leu10Ile Uncertain significance ★ ⚠ same type
COX7B2 p.Leu19Pro Uncertain significance ★ ⚠ same type
COX7B2 p.Met22Val Uncertain significance ★ ⚠ same type
COX7B2 p.Ser31Leu 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/cox7b2-p-pro75gln (accessed [today's date]).

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