Is HSF4 p.Leu447= (c.1341C>G) pathogenic?

HSF4 p.Leu447= (c.1341C>G) is classified Benign/Likely benign in HSF4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-01). Rare (popmax 0.805%, afr); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Leu447= (c.1341C>G)?

HSF4 p.Leu447= (c.1341C>G) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Leu447= (c.1341C>G) in the general population?

HSF4 p.Leu447= (c.1341C>G) is rare (popmax 0.805%, 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.Leu447=

c.1341C>G · rs35750776 · VCV1166869

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.805%, afr)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.02	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -3.5
Overall
CADD	0.194	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.805% African / African-American · 604/75,036 alleles

Filtering AF 0.752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.731%

Overall 0.0407% 655/1,609,560 alleles · rare exomes 285/1,457,278 · genomes 370/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.805%	124
Remaining individualsnot grpmax-eligible	0.0416%	2,403
Admixed American	0.04%	2,501
European (non-Finnish)	8.47e-05%	1,179,958

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.Leu447=
Coding: c.1341C>G
MANE Select: NM_001374675
dbSNP: rs35750776
Type: single nucleotide variant
Location: chr16:67169647 (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.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-leu447 (accessed [today's date]).

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