Is HSF4 p.Pro378Ser (c.1132C>T) pathogenic?

HSF4 p.Pro378Ser (c.1132C>T) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0821); Ultra-rare (popmax 0.0893%, afr); Associated with Inborn genetic diseases.

What condition is associated with HSF4 p.Pro378Ser (c.1132C>T)?

HSF4 p.Pro378Ser (c.1132C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HSF4 p.Pro378Ser (c.1132C>T) in the general population?

HSF4 p.Pro378Ser (c.1132C>T) is ultra-rare (popmax 0.0893%, afr) (gnomAD).

What do computational predictors say about HSF4 p.Pro378Ser (c.1132C>T)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

HSF4 p.Pro378Ser

c.1132C>T · rs183968834 · VCV3033052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -5.96	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 1.1	GERP -0.45, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	15.81	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0893% African / African-American · 67/75,044 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.00452% 73/1,614,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0893%	1,120
Admixed American	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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.Pro378Ser
Coding: c.1132C>T
MANE Select: NM_001374675
dbSNP: rs183968834
Type: single nucleotide variant
Location: chr16:67168880 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 378: the 'disordered' region; the 'hydrophobic repeat hr-c' region

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

Similar variants

HSF4 p.Ala320Gly Uncertain significance ★★ ⚠ same condition
HSF4 p.Ala432Val Uncertain significance ★★ ⚠ same condition
HSF4 p.Glu115Gly Uncertain significance ★★ ⚠ same condition
HSF4 p.Gly13Asp Uncertain significance ★★ ⚠ same condition
HSF4 p.Gly442Glu Uncertain significance ★★ ⚠ same condition
HSF4 p.Ile86Thr Uncertain significance ★★ ⚠ same condition
HSF4 p.Met68Thr Uncertain significance ★★ ⚠ same condition
HSF4 p.Ser269Phe 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-pro378ser (accessed [today's date]).

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