Is COX6C p.Arg40His (c.119G>A) pathogenic?

COX6C p.Arg40His (c.119G>A) is classified Uncertain significance in COX6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1205); Ultra-rare (popmax 0.0488%, sas).

How common is COX6C p.Arg40His (c.119G>A) in the general population?

COX6C p.Arg40His (c.119G>A) is ultra-rare (popmax 0.0488%, sas) (gnomAD).

What do computational predictors say about COX6C p.Arg40His (c.119G>A)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

COX6C p.Arg40His

c.119G>A · rs746221706 · VCV2378784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0488%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.021	GERP -4.3, phastCons 0.072
Regional constraint	o/e 1.04	unconstrained · MANE · 4,513 bp · p 0.71 · regional, not allelic
Overall
CADD	10.57	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 0.0488% South Asian · 42/86,112 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0329%

Overall 0.00573% 91/1,589,006 alleles · ultra-rare exomes 89/1,437,002 · genomes 2/152,004 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0488%	2,050
Admixed American	0.00561%	17,837
Remaining individualsnot grpmax-eligible	0.00489%	20,467
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,678
European (non-Finnish)	0.00341%	29,292
African / African-American	0.00275%	36,399

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: COX6C
Protein: p.Arg40His
Coding: c.119G>A
MANE Select: NM_004374
dbSNP: rs746221706
Type: single nucleotide variant
Location: chr8:99887614 (GRCh38)
Gene constraint: LOEUF 1.231 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 94.94 · 3 PDB

Full COX6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX6C p.Ala16Ser Uncertain significance ★ ⚠ same type
COX6C p.Arg18His Uncertain significance ★ ⚠ same type
COX6C p.Arg66Lys Uncertain significance ★ ⚠ same type
COX6C p.Asn21Ser Uncertain significance ★ ⚠ same type
COX6C p.Glu4Gln Uncertain significance ★ ⚠ same type
COX6C p.Glu64Asp Uncertain significance ★ ⚠ same type
COX6C p.Lys8Glu Uncertain significance ★ ⚠ same type
COX6C p.Met11Ile 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/cox6c-p-arg40his (accessed [today's date]).

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