Is COX6A1 p.Arg17Cys (c.49C>T) pathogenic?

COX6A1 p.Arg17Cys (c.49C>T) is classified Uncertain significance in COX6A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1976); Very rare (popmax 0.00167%, amr).

How common is COX6A1 p.Arg17Cys (c.49C>T) in the general population?

COX6A1 p.Arg17Cys (c.49C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about COX6A1 p.Arg17Cys (c.49C>T)?

AlphaMissense predicts likely benign (score 0.1976) — an in-silico prediction, not a clinical call.

COX6A1 p.Arg17Cys

c.49C>T · VCV4006001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1976	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.90	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 0.28	GERP -0.25
Regional constraint	o/e 1.01	unconstrained · MANE · 2,407 bp · p 0.91 · regional, not allelic
Overall
CADD	20.5	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 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,760 alleles · very rare exomes 3/1,461,560 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,410
European (non-Finnish)	0.000169%	589,981

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: COX6A1
Protein: p.Arg17Cys
Coding: c.49C>T
MANE Select: NM_004373
Type: single nucleotide variant
Location: chr12:120438175 (GRCh38)
Gene constraint: LOEUF 1.355 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.06 · 3 PDB

Full COX6A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX6A1 p.Arg17His Uncertain significance ★★ ⚠ same residue
COX6A1 c.103+1G>C Uncertain significance ★★ same type
COX6A1 p.Ala2Ser Uncertain significance ★★ ⚠ same type
COX6A1 p.Arg11Pro Uncertain significance ★★ ⚠ same type
COX6A1 p.Arg36Cys Uncertain significance ★★ ⚠ same type
COX6A1 p.Glu107Lys Uncertain significance ★★ ⚠ same type
COX6A1 p.His62Tyr Uncertain significance ★★ ⚠ same type
COX6A1 p.His98Tyr 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/cox6a1-p-arg17cys (accessed [today's date]).

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