Is ENOX2 p.Cys481Arg (c.1441T>C) pathogenic?

ENOX2 p.Cys481Arg (c.1441T>C) is classified Uncertain significance in ENOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.1805); Very rare (popmax 0.00174%, afr).

How common is ENOX2 p.Cys481Arg (c.1441T>C) in the general population?

ENOX2 p.Cys481Arg (c.1441T>C) is very rare (popmax 0.00174%, afr) (gnomAD).

What do computational predictors say about ENOX2 p.Cys481Arg (c.1441T>C)?

AlphaMissense predicts likely benign (score 0.1805) — an in-silico prediction, not a clinical call.

ENOX2 p.Cys481Arg

c.1441T>C · VCV3275464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1805	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -5.13	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 7.7	GERP 0.79, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 5,857 bp · p 8.4e-06 · regional, not allelic
Overall
CADD	14.88	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C510R vs ClinVar C481R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% African / African-American · 1/57,407 alleles

Overall 9.29e-05% 1/1,076,919 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: ENOX2
Protein: p.Cys481Arg
Coding: c.1441T>C
MANE Select: NM_006375
Type: single nucleotide variant
Location: chrX:130631555 (GRCh38)
Structure: AlphaFold pLDDT 77.86

Full ENOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENOX2 c.1129+6G>A Benign ★★ same type
ENOX2 c.-38-6023T>G Uncertain significance ★ ⚠ same type
ENOX2 p.Arg129His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg139His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg156His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg190His Uncertain significance ★ ⚠ same type
ENOX2 p.Arg190Leu Uncertain significance ★ ⚠ same type
ENOX2 p.Arg208His 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/enox2-p-cys481arg (accessed [today's date]).

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