Is COX6A2 p.Pro71Ser (c.211C>T) pathogenic?

COX6A2 p.Pro71Ser (c.211C>T) is classified Uncertain significance in COX6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.238); Very rare (popmax 0.000657%, nfe).

How common is COX6A2 p.Pro71Ser (c.211C>T) in the general population?

COX6A2 p.Pro71Ser (c.211C>T) is very rare (popmax 0.000657%, nfe) (gnomAD).

What do computational predictors say about COX6A2 p.Pro71Ser (c.211C>T)?

AlphaMissense predicts likely benign (score 0.238) — an in-silico prediction, not a clinical call.

COX6A2 p.Pro71Ser

c.211C>T · VCV4233025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.238 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000657%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.238	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -11.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.72, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 548 bp · p 0.002 · regional, not allelic
Overall
CADD	24.6	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 0.000657% European (non-Finnish) · 7/1,065,720 alleles

Filtering AF 0.000273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000176%

Overall 0.000505% 7/1,385,924 alleles · very rare

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: COX6A2
Protein: p.Pro71Ser
Coding: c.211C>T
MANE Select: NM_005205
Type: single nucleotide variant
Location: chr16:31427857 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30

Full COX6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX6A2 p.Pro71His Uncertain significance ★ same residue
COX6A2 p.Leu81Val Uncertain significance ★★ ⚠ same type
COX6A2 p.Ser39Arg Likely pathogenic ★ ⚠ same type
COX6A2 p.Ala2Thr Uncertain significance ★ ⚠ same type
COX6A2 p.Arg54Leu Uncertain significance ★ ⚠ same type
COX6A2 p.Arg60Cys Uncertain significance ★ ⚠ same type
COX6A2 p.Arg66Gly Uncertain significance ★ ⚠ same type
COX6A2 p.Arg68His 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/cox6a2-p-pro71ser (accessed [today's date]).

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