Is HSF4 p.Asp302fs (c.904del) pathogenic?

HSF4 p.Asp302fs (c.904del) is classified Likely pathogenic in HSF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-02). Very rare (popmax 0.00669%, afr); Associated with HSF4-related disorder.

What condition is associated with HSF4 p.Asp302fs (c.904del)?

HSF4 p.Asp302fs (c.904del) is associated with HSF4-related disorder (ClinVar).

How common is HSF4 p.Asp302fs (c.904del) in the general population?

HSF4 p.Asp302fs (c.904del) is very rare (popmax 0.00669%, afr) (gnomAD).

HSF4 p.Asp302fs

c.904del · rs760309963 · VCV2634990

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Conditions

HSF4-related disorder

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 2.6	GERP 0.63, phastCons 1
Overall
CADD	33.0	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 0.00669% African / African-American · 5/74,772 alleles

Filtering AF 0.00319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00411% 66/1,605,496 alleles · very rare exomes 60/1,453,316 · genomes 6/152,180 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0113%	8,871
African / African-Americangrpmax	0.00669%	14,954
East Asian	0.00448%	22,325
European (non-Finnish)	0.00416%	24,011
South Asian	0.00221%	45,200
Remaining individualsnot grpmax-eligible	0.00161%	62,136

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.Asp302fs
Coding: c.904del
MANE Select: NM_001374675
dbSNP: rs760309963
Type: Deletion
Location: chr16:67167763 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 302: the 'interactions with dusp26, mapk1 and mapk2' region

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

Disease context

HSF4-related disorder

Similar variants

HSF4 p.Gln330fs Likely pathogenic ★ same condition
HSF4 p.Arg119Cys Pathogenic ★ same condition
HSF4 p.Gln112Ter Likely pathogenic ★ same condition
HSF4 p.Glu3Ter Likely pathogenic ★ same condition
HSF4 c.562-1G>C Uncertain significance ★ same condition
HSF4 p.Ala145_Gln150dup Conflicting classifications of pathogenicity ★ same condition
HSF4 p.Leu136Val Uncertain significance ★ ⚠ same condition
HSF4 p.Arg118Gly 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-asp302fs (accessed [today's date]).

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