Is COX6A1 p.Ser7Cys (c.20C>G) pathogenic?

COX6A1 p.Ser7Cys (c.20C>G) is classified Uncertain significance in COX6A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-15). AlphaMissense: likely benign (0.1033); Ultra-rare (popmax 0.0143%, sas).

How common is COX6A1 p.Ser7Cys (c.20C>G) in the general population?

COX6A1 p.Ser7Cys (c.20C>G) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about COX6A1 p.Ser7Cys (c.20C>G)?

AlphaMissense predicts likely benign (score 0.1033) — an in-silico prediction, not a clinical call.

COX6A1 p.Ser7Cys

c.20C>G · rs375856274 · VCV1444102

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1033 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1033	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.53	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 -0.068	GERP -2.8
Regional constraint	o/e 1.01	unconstrained · MANE · 2,407 bp · p 0.91 · regional, not allelic
Overall
CADD	11.85	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 0.0143% South Asian · 13/91,048 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.0026% 42/1,613,560 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,004
Admixed American	0.00834%	11,995
Remaining individualsnot grpmax-eligible	0.00801%	12,480
European (non-Finnish)	0.00161%	62,101

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.Ser7Cys
Coding: c.20C>G
MANE Select: NM_004373
dbSNP: rs375856274
Type: single nucleotide variant
Location: chr12:120438146 (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.Ser7Phe Uncertain significance ★★ ⚠ same residue
COX6A1 p.Ser7Thr Uncertain significance ★★ ⚠ same residue
COX6A1 p.Ser7Pro Uncertain significance ★ ⚠ same residue
COX6A1 p.Ser7= Likely benign ★ 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.Arg17His 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-ser7cys (accessed [today's date]).

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