Is COX6B2 p.Arg48Cys (c.142C>T) pathogenic?

COX6B2 p.Arg48Cys (c.142C>T) is classified Uncertain significance in COX6B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1378); Ultra-rare (popmax 0.0192%, eas).

How common is COX6B2 p.Arg48Cys (c.142C>T) in the general population?

COX6B2 p.Arg48Cys (c.142C>T) is ultra-rare (popmax 0.0192%, eas) (gnomAD).

What do computational predictors say about COX6B2 p.Arg48Cys (c.142C>T)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

COX6B2 p.Arg48Cys

c.142C>T · VCV4006008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 797 bp · p 0.28 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0192% East Asian · 8/41,606 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.000962% 15/1,559,012 alleles · ultra-rare exomes 15/1,406,766 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0192%	5,201
Middle Eastern	0.0174%	5,758
South Asian	0.00117%	85,196
European (non-Finnish)	0.000433%	230,855

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.Arg48Cys
Coding: c.142C>T
MANE Select: NM_144613
Type: single nucleotide variant
Location: chr19:55353937 (GRCh38)
Gene constraint: LOEUF 1.606 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.53
Residue 48: the chch domain

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.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.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-arg48cys (accessed [today's date]).

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