Is COX6A2 p.Pro38Ser (c.112C>T) pathogenic?

COX6A2 p.Pro38Ser (c.112C>T) is classified Uncertain significance in COX6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.8019); Very rare (popmax 0.00187%, amr).

How common is COX6A2 p.Pro38Ser (c.112C>T) in the general population?

COX6A2 p.Pro38Ser (c.112C>T) is very rare (popmax 0.00187%, amr) (gnomAD).

What do computational predictors say about COX6A2 p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely pathogenic (score 0.8019) — an in-silico prediction, not a clinical call.

COX6A2 p.Pro38Ser

c.112C>T · VCV3835715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8019	likely pathogenic
REVEL	0.738	pathogenic-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 548 bp · p 0.002 · regional, not allelic
Overall
CADD	29.9	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 0.00187% Admixed American · 1/53,408 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000212% 3/1,416,930 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00187%	53,408
European (non-Finnish)	0.000173%	579,106

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.Pro38Ser
Coding: c.112C>T
MANE Select: NM_005205
Type: single nucleotide variant
Location: chr16:31428113 (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.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
COX6A2 p.Asn46Ile 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-pro38ser (accessed [today's date]).

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