Is COX10 p.Phe83Leu (c.249C>G) pathogenic?

COX10 p.Phe83Leu (c.249C>G) is classified Uncertain significance in COX10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.4293); Ultra-rare (popmax 0.0666%, afr); Associated with Inborn genetic diseases.

What condition is associated with COX10 p.Phe83Leu (c.249C>G)?

COX10 p.Phe83Leu (c.249C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COX10 p.Phe83Leu (c.249C>G) in the general population?

COX10 p.Phe83Leu (c.249C>G) is ultra-rare (popmax 0.0666%, afr) (gnomAD).

What do computational predictors say about COX10 p.Phe83Leu (c.249C>G)?

AlphaMissense predicts ambiguous (score 0.4293) — an in-silico prediction, not a clinical call.

COX10 p.Phe83Leu

c.249C>G · rs375765781 · VCV2069002

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4293 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4293	ambiguous
REVEL	0.127	moderately benign-leaning
SaProt	LLR -4.51	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP 2.2, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.97 · regional, not allelic
Overall
CADD	16.99	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0666% African / African-American · 50/75,030 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.0031% 50/1,614,112 alleles · ultra-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: COX10
Protein: p.Phe83Leu
Coding: c.249C>G
MANE Select: NM_001303
dbSNP: rs375765781
Type: single nucleotide variant
Location: chr17:14076806 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.11

Full COX10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COX10 p.Ala175Ser Uncertain significance ★★ ⚠ same condition
COX10 p.Ala303Asp Uncertain significance ★★ ⚠ same condition
COX10 p.Arg334His Uncertain significance ★★ ⚠ same condition
COX10 p.Arg398Cys Uncertain significance ★★ ⚠ same condition
COX10 p.Asp308Asn Uncertain significance ★★ ⚠ same condition
COX10 p.Glu25Gly Uncertain significance ★★ ⚠ same condition
COX10 p.Gly434Arg Uncertain significance ★★ ⚠ same condition
COX10 p.Gly436Arg Uncertain significance ★★ ⚠ same condition

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/cox10-p-phe83leu (accessed [today's date]).

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