Is HSF4 p.Arg118Pro (c.353G>C) pathogenic?

HSF4 p.Arg118Pro (c.353G>C) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.9076); Absent from gnomAD v4.1; Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Arg118Pro (c.353G>C)?

HSF4 p.Arg118Pro (c.353G>C) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Arg118Pro (c.353G>C) in the general population?

HSF4 p.Arg118Pro (c.353G>C) is absent from gnomAD v4.1 (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HSF4 p.Arg118Pro (c.353G>C)?

AlphaMissense predicts likely pathogenic (score 0.9076) — an in-silico prediction, not a clinical call.

HSF4 p.Arg118Pro

c.353G>C · rs1336923341 · VCV1999411

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9076 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 5 multiple types

Computational evidence

Protein change
AlphaMissense	0.9076	likely pathogenic
REVEL	0.673	pathogenic-leaning
SaProt	LLR -14.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: HSF4
Protein: p.Arg118Pro
Coding: c.353G>C
MANE Select: NM_001374675
dbSNP: rs1336923341
Type: single nucleotide variant
Location: chr16:67165839 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 118: a DNA-binding region

Full HSF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 5 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

HSF4 p.Arg118Trp Likely pathogenic ★ same residue
HSF4 p.Arg118Gln Uncertain significance ★ ⚠ same residue
HSF4 p.Arg118Gly Uncertain significance ⚠ same residue
HSF4 p.Ala432Val Uncertain significance ★★ ⚠ same condition
HSF4 p.Arg108Ser Uncertain significance ★★ ⚠ same condition
HSF4 p.Glu115Gly Uncertain significance ★★ ⚠ same condition
HSF4 p.Glu247= Uncertain significance ★★ same condition
HSF4 p.Glu3Gly 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/hsf4-p-arg118pro (accessed [today's date]).

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