Is HSF4 p.Pro379= (c.1137G>A) pathogenic?

HSF4 p.Pro379= (c.1137G>A) is classified Likely benign in HSF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-13). Very rare (popmax 0.00788%, nfe); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Pro379= (c.1137G>A)?

HSF4 p.Pro379= (c.1137G>A) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Pro379= (c.1137G>A) in the general population?

HSF4 p.Pro379= (c.1137G>A) is very rare (popmax 0.00788%, nfe) (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.

HSF4 p.Pro379=

c.1137G>A · rs369862977 · VCV320189

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -3.2
Overall
CADD	3.586	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00788% European (non-Finnish) · 93/1,180,030 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00595% 96/1,613,900 alleles · very rare exomes 94/1,461,712 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00788%	12,688
African / African-American	0.00267%	37,467
Admixed American	0.00167%	60,000

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.Pro379=
Coding: c.1137G>A
MANE Select: NM_001374675
dbSNP: rs369862977
Type: single nucleotide variant
Location: chr16:67168885 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 379: the 'disordered' region; the 'hydrophobic repeat hr-c' 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-pro379 (accessed [today's date]).

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