Is HSF4 p.His178= (c.534C>T) pathogenic?

HSF4 p.His178= (c.534C>T) is classified Likely benign in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). Rare (popmax 0.131%, afr); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.His178= (c.534C>T)?

HSF4 p.His178= (c.534C>T) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.His178= (c.534C>T) in the general population?

HSF4 p.His178= (c.534C>T) is rare (popmax 0.131%, 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.His178=

c.534C>T · VCV3712364

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.019	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.1	GERP -3.5
Overall
CADD	3.949	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% African / African-American · 98/74,842 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.00702% 113/1,609,598 alleles · rare exomes 54/1,457,506 · genomes 59/152,092 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	764
Remaining individualsnot grpmax-eligible	0.00963%	10,389
Admixed American	0.0084%	11,910
South Asian	0.00221%	45,180
European (non-Finnish)	0.00017%	589,018

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.His178=
Coding: c.534C>T
MANE Select: NM_001374675
Type: single nucleotide variant
Location: chr16:67166368 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 178: the 'hydrophobic repeat hr-a/b' 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-his178 (accessed [today's date]).

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