Is HSF4 p.Ile86Val (c.256A>G) pathogenic?

HSF4 p.Ile86Val (c.256A>G) is classified Pathogenic in HSF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-07-01). AlphaMissense: likely benign (0.139); Absent from gnomAD v4.1; Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Ile86Val (c.256A>G)?

HSF4 p.Ile86Val (c.256A>G) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Ile86Val (c.256A>G) in the general population?

HSF4 p.Ile86Val (c.256A>G) is absent from gnomAD v4.1 (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.

What do computational predictors say about HSF4 p.Ile86Val (c.256A>G)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

HSF4 p.Ile86Val

c.256A>G · rs121909050 · VCV7095

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cataract 5 multiple types

Computational evidence

Protein change
AlphaMissense	0.139	likely benign ⚠ discordant with ClinVar
REVEL	0.49	indeterminate
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HSF4
Protein: p.Ile86Val
Coding: c.256A>G
MANE Select: NM_001374675
dbSNP: rs121909050
Type: single nucleotide variant
Location: chr16:67165742 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 86: a DNA-binding region; a UniProt-annotated variant site (in ctrct5; sporadic)

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.Ile86Thr Uncertain significance ★★ ⚠ same residue
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

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-ile86val (accessed [today's date]).

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