Is HSF4 p.Pro344Ser (c.1030C>T) pathogenic?

HSF4 p.Pro344Ser (c.1030C>T) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-11). AlphaMissense: likely benign (0.0887); Very rare (popmax 0.00169%, amr); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Pro344Ser (c.1030C>T)?

HSF4 p.Pro344Ser (c.1030C>T) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Pro344Ser (c.1030C>T) in the general population?

HSF4 p.Pro344Ser (c.1030C>T) is very rare (popmax 0.00169%, amr) (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.Pro344Ser (c.1030C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

HSF4 p.Pro344Ser

c.1030C>T · rs932918368 · VCV1433465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 5 multiple types

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -6.39	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 2.6	GERP 0.74, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	19.47	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 0.00169% Admixed American · 1/59,302 alleles

Overall 0.000138% 2/1,452,414 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,302
Remaining individualsnot grpmax-eligible	0.00161%	62,244

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.Pro344Ser
Coding: c.1030C>T
MANE Select: NM_001374675
dbSNP: rs932918368
Type: single nucleotide variant
Location: chr16:67167895 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 344: the 'disordered' 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.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
HSF4 p.Gly13Asp Uncertain significance ★★ ⚠ same condition
HSF4 p.Gly399Asp Uncertain significance ★★ ⚠ same condition
HSF4 p.His98Leu 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-pro344ser (accessed [today's date]).

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