Is COX6B2 p.Cys56Phe (c.167G>T) pathogenic?

COX6B2 p.Cys56Phe (c.167G>T) is classified Uncertain significance in COX6B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.4705); Ultra-rare (popmax 0.0135%, afr).

How common is COX6B2 p.Cys56Phe (c.167G>T) in the general population?

COX6B2 p.Cys56Phe (c.167G>T) is ultra-rare (popmax 0.0135%, afr) (gnomAD).

What do computational predictors say about COX6B2 p.Cys56Phe (c.167G>T)?

AlphaMissense predicts ambiguous (score 0.4705) — an in-silico prediction, not a clinical call.

COX6B2 p.Cys56Phe

c.167G>T · VCV4233027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4705	ambiguous
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -12.52	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 797 bp · p 0.28 · regional, not allelic
Overall
CADD	27.8	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 0.0135% African / African-American · 10/73,868 alleles

Filtering AF 0.00732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.000637% 10/1,571,016 alleles · ultra-rare exomes 3/1,418,834 · genomes 7/152,182 · joint denominator

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: COX6B2
Protein: p.Cys56Phe
Coding: c.167G>T
MANE Select: NM_144613
Type: single nucleotide variant
Location: chr19:55353912 (GRCh38)
Gene constraint: LOEUF 1.606 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.53
Residue 56: the chch domain; a disulfide bond

Full COX6B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX6B2 p.Arg30Cys Uncertain significance ★ ⚠ same type
COX6B2 p.Arg48Cys Uncertain significance ★ ⚠ same type
COX6B2 p.Asn27Lys Uncertain significance ★ same type
COX6B2 p.Gln28Lys Uncertain significance ★ ⚠ same type
COX6B2 p.Gly86Ser Uncertain significance ★ ⚠ same type
COX6B2 p.His40Arg Uncertain significance ★ ⚠ same type
COX6B2 p.His40Tyr Uncertain significance ★ ⚠ same type
COX6B2 p.Lys13Ile 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/cox6b2-p-cys56phe (accessed [today's date]).

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