Is COX6A1 p.Val4Phe (c.10G>T) pathogenic?

COX6A1 p.Val4Phe (c.10G>T) is classified Uncertain significance in COX6A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0959); Very rare (popmax 0.00144%, nfe).

How common is COX6A1 p.Val4Phe (c.10G>T) in the general population?

COX6A1 p.Val4Phe (c.10G>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about COX6A1 p.Val4Phe (c.10G>T)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

COX6A1 p.Val4Phe

c.10G>T · rs952531441 · VCV1363414

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP -3, phastCons 0.14
Regional constraint	o/e 1.01	unconstrained · MANE · 2,407 bp · p 0.91 · regional, not allelic
Overall
CADD	13.15	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 0.00144% European (non-Finnish) · 17/1,179,896 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00118% 19/1,613,378 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)grpmax	0.00144%	69,406

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val4Phe
Coding: c.10G>T
MANE Select: NM_004373
dbSNP: rs952531441
Type: single nucleotide variant
Location: chr12:120438136 (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.Val4Gly 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.Arg17His 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

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-val4phe (accessed [today's date]).

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