Is COX8C p.Val46Ile (c.136G>A) pathogenic?

COX8C p.Val46Ile (c.136G>A) is classified Uncertain significance in COX8C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1291); Very rare (popmax 8.51e-05%, nfe).

How common is COX8C p.Val46Ile (c.136G>A) in the general population?

COX8C p.Val46Ile (c.136G>A) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about COX8C p.Val46Ile (c.136G>A)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

COX8C p.Val46Ile

c.136G>A · VCV4655981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -7.95	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 -1.7	GERP -3
Regional constraint	o/e 1.10	unconstrained · MANE · 848 bp · p 0.3 · regional, not allelic
Overall
CADD	9.271	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 8.51e-05% European (non-Finnish) · 1/1,174,428 alleles

Overall 6.87e-05% 1/1,455,734 alleles · very rare

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: COX8C
Protein: p.Val46Ile
Coding: c.136G>A
MANE Select: NM_182971
Type: single nucleotide variant
Location: chr14:93348037 (GRCh38)
Gene constraint: LOEUF 1.876 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 78.94

Full COX8C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX8C p.Val46Ala Uncertain significance ★ ⚠ same residue
COX8C c.127-2A>G Uncertain significance ★ same type
COX8C p.Ala10Ser Uncertain significance ★ ⚠ same type
COX8C p.Arg11Cys Uncertain significance ★ ⚠ same type
COX8C p.Arg12Ser Uncertain significance ★ ⚠ same type
COX8C p.Arg15Cys Uncertain significance ★ ⚠ same type
COX8C p.Arg15Ser Uncertain significance ★ ⚠ same type
COX8C p.Arg16Cys 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/cox8c-p-val46ile (accessed [today's date]).

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