Is COX6B2 p.His40Arg (c.119A>G) pathogenic?

COX6B2 p.His40Arg (c.119A>G) is classified Uncertain significance in COX6B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.1234); Ultra-rare (popmax 0.0205%, afr).

How common is COX6B2 p.His40Arg (c.119A>G) in the general population?

COX6B2 p.His40Arg (c.119A>G) is ultra-rare (popmax 0.0205%, afr) (gnomAD).

What do computational predictors say about COX6B2 p.His40Arg (c.119A>G)?

AlphaMissense predicts likely benign (score 0.1234) — an in-silico prediction, not a clinical call.

COX6B2 p.His40Arg

c.119A>G · VCV4006007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1234 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1234	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -11.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP 1.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 797 bp · p 0.28 · regional, not allelic
Overall
CADD	21.8	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 0.0205% African / African-American · 15/73,120 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00129% 20/1,546,578 alleles · ultra-rare exomes 11/1,394,708 · genomes 9/151,870 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0205%	4,875
Admixed American	0.00388%	25,793
European (non-Finnish)	0.000261%	383,333

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.His40Arg
Coding: c.119A>G
MANE Select: NM_144613
Type: single nucleotide variant
Location: chr19:55353960 (GRCh38)
Gene constraint: LOEUF 1.606 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.53
Residue 40: the chch domain

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

Similar variants

COX6B2 p.His40Tyr Uncertain significance ★ ⚠ same residue
COX6B2 p.Arg30Cys Uncertain significance ★ ⚠ same type
COX6B2 p.Arg48Cys Uncertain significance ★ ⚠ same type
COX6B2 p.Asn27Lys Uncertain significance ★ same type
COX6B2 p.Cys56Phe Uncertain significance ★ ⚠ same type
COX6B2 p.Gln28Lys Uncertain significance ★ ⚠ same type
COX6B2 p.Gly86Ser 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-his40arg (accessed [today's date]).

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