Is HUWE1 p.His4135Pro (c.12404A>C) pathogenic?

HUWE1 p.His4135Pro (c.12404A>C) is classified Pathogenic in HUWE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.9964); Absent from gnomAD v4.1; Associated with intellectual disability, X-linked syndromic, Turner type.

What condition is associated with HUWE1 p.His4135Pro (c.12404A>C)?

HUWE1 p.His4135Pro (c.12404A>C) is associated with intellectual disability, X-linked syndromic, Turner type (ClinVar).

How common is HUWE1 p.His4135Pro (c.12404A>C) in the general population?

HUWE1 p.His4135Pro (c.12404A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HUWE1 p.His4135Pro (c.12404A>C)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

HUWE1 p.His4135Pro

c.12404A>C · rs2146878120 · VCV1320047

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intellectual disability, X-linked syndromic, Turner type

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic ✓ concordant with ClinVar
REVEL	0.569	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 6,447 bp · p 1.3e-49 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HUWE1
Protein: p.His4135Pro
Coding: c.12404A>C
MANE Select: NM_031407
dbSNP: rs2146878120
Type: single nucleotide variant
Location: chrX:53536401 (GRCh38)
Residue 4135: an α-helix; the hect domain

Full HUWE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked syndromic, Turner type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HUWE1 p.His4135Gln Uncertain significance ★ same residue
HUWE1 c.567+1G>C Pathogenic ★★ same condition
HUWE1 p.Arg110Gln Pathogenic ★★ same condition
HUWE1 p.Arg2981His Pathogenic/Likely pathogenic ★★ same condition
HUWE1 p.Arg3070Cys Pathogenic/Likely pathogenic ★★ same condition
HUWE1 p.Arg3070His Pathogenic ★★ same condition
HUWE1 p.Arg4013Trp Pathogenic/Likely pathogenic ★★ same condition
HUWE1 p.Gly4217Ala Likely pathogenic ★★ 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/huwe1-p-his4135pro (accessed [today's date]).

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