Is HSF4 p.Pro323fs (c.965dup) pathogenic?

HSF4 p.Pro323fs (c.965dup) is classified Pathogenic in HSF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). Very rare (popmax 0.00807%, afr); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Pro323fs (c.965dup)?

HSF4 p.Pro323fs (c.965dup) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Pro323fs (c.965dup) in the general population?

HSF4 p.Pro323fs (c.965dup) is very rare (popmax 0.00807%, afr) (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.Pro323fs

c.965dup · rs776129797 · VCV567423

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00807%, afr)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00807% African / African-American · 6/74,356 alleles

Filtering AF 0.00406% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00365%

Overall 0.00605% 96/1,586,996 alleles · very rare exomes 85/1,434,854 · genomes 11/152,142 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0333%	3,000
African / African-Americangrpmax	0.00807%	12,393
Remaining individualsnot grpmax-eligible	0.00651%	15,354
Admixed American	0.00539%	18,543
European (non-Finnish)	0.00514%	19,462
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,146
East Asian	0.0023%	43,448
South Asian	0.00113%	88,392

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro323fs
Coding: c.965dup
MANE Select: NM_001374675
dbSNP: rs776129797
Type: Duplication
Location: chr16:67167823 (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.Gln180fs Pathogenic ★ same condition
HSF4 p.Glu425fs Pathogenic ★ same condition
HSF4 p.Ala145_Gln150dup Conflicting classifications of pathogenicity ★ same condition
HSF4 p.Ser388fs Uncertain significance ★ same condition
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

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-pro323fs (accessed [today's date]).

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