Is HSF4 p.Pro492Arg (c.1475C>G) pathogenic?

HSF4 p.Pro492Arg (c.1475C>G) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-08). AlphaMissense: likely benign (0.075); Ultra-rare (popmax 0.0357%, eas); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Pro492Arg (c.1475C>G)?

HSF4 p.Pro492Arg (c.1475C>G) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Pro492Arg (c.1475C>G) in the general population?

HSF4 p.Pro492Arg (c.1475C>G) is ultra-rare (popmax 0.0357%, eas) (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.Pro492Arg (c.1475C>G)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

HSF4 p.Pro492Arg

c.1475C>G · rs182365484 · VCV2048803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 5 multiple types

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.75	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 0.24	GERP 0.69
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	17.05	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 0.0357% East Asian · 16/44,872 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00527% 85/1,613,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,804
South Asian	0.0253%	3,960
Admixed American	0.0167%	6,002
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0112%	8,928
European (non-Finnish)	0.0022%	45,385
Finnishnot grpmax-eligible	0.00159%	63,036
African / African-American	0.00133%	75,038

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: HSF4
Protein: p.Pro492Arg
Coding: c.1475C>G
MANE Select: NM_001374675
dbSNP: rs182365484
Type: single nucleotide variant
Location: chr16:67169781 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB

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.Pro492= Benign/Likely benign ★★ same residue
HSF4 p.Pro492Leu Uncertain significance ★ ⚠ same residue
HSF4 p.Pro492His Benign ★ 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-pro492arg (accessed [today's date]).

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