Is HSF4 p.Pro439Ser (c.1315C>T) pathogenic?

HSF4 p.Pro439Ser (c.1315C>T) is classified Conflicting classifications of pathogenicity in HSF4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-26). AlphaMissense: likely benign (0.0682); Rare (popmax 0.1%, eas); Associated with Inborn genetic diseases.

What condition is associated with HSF4 p.Pro439Ser (c.1315C>T)?

HSF4 p.Pro439Ser (c.1315C>T) is associated with Inborn genetic diseases, cataract 5 multiple types (ClinVar).

How common is HSF4 p.Pro439Ser (c.1315C>T) in the general population?

HSF4 p.Pro439Ser (c.1315C>T) is rare (popmax 0.1%, eas) (gnomAD).

What do computational predictors say about HSF4 p.Pro439Ser (c.1315C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

HSF4 p.Pro439Ser

c.1315C>T · rs777720209 · VCV886550

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.66, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	17.75	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

Grpmax group 0.1% East Asian · 45/44,882 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00304% 49/1,613,236 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	997
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.000254%	393,283

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.Pro439Ser
Coding: c.1315C>T
MANE Select: NM_001374675
dbSNP: rs777720209
Type: single nucleotide variant
Location: chr16:67169339 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cataract 5 multiple types

Similar variants

HSF4 p.Ala320Gly Uncertain significance ★★ ⚠ same condition
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-pro439ser (accessed [today's date]).

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