Is HSF4 p.Ile166= (c.498C>T) pathogenic?

HSF4 p.Ile166= (c.498C>T) is classified Likely benign in HSF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). Ultra-rare (popmax 0.0618%, amr); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Ile166= (c.498C>T)?

HSF4 p.Ile166= (c.498C>T) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Ile166= (c.498C>T) in the general population?

HSF4 p.Ile166= (c.498C>T) is ultra-rare (popmax 0.0618%, 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.

HSF4 p.Ile166=

c.498C>T · VCV4768228

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0618%, amr)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.127	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -1.2, phastCons 0.93
Overall
CADD	11.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0618% Admixed American · 37/59,842 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0406%

Overall 0.024% 387/1,612,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0618%	1,617
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0288%	3,468
European (non-Finnish)	0.0258%	3,879
Finnishnot grpmax-eligible	0.0141%	7,088
South Asian	0.0121%	8,251
African / African-American	0.008%	12,492

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.Ile166=
Coding: c.498C>T
MANE Select: NM_001374675
Type: single nucleotide variant
Location: chr16:67166332 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 166: 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-ile166 (accessed [today's date]).

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