Is HSF4 p.Ser52Arg (c.156C>A) pathogenic?

HSF4 p.Ser52Arg (c.156C>A) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-18). AlphaMissense: likely pathogenic (0.9022); Absent from gnomAD v4.1.

How common is HSF4 p.Ser52Arg (c.156C>A) in the general population?

HSF4 p.Ser52Arg (c.156C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HSF4 p.Ser52Arg (c.156C>A)?

AlphaMissense predicts likely pathogenic (score 0.9022) — an in-silico prediction, not a clinical call.

HSF4 p.Ser52Arg

c.156C>A · rs1202155431 · VCV1705131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9022 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9022	likely pathogenic
REVEL	0.395	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,970 bp · p 0.11 · regional, not allelic
Overall
CADD	24.0	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.Ser52Arg
Coding: c.156C>A
MANE Select: NM_001374675
dbSNP: rs1202155431
Type: single nucleotide variant
Location: chr16:67165554 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 52: a DNA-binding region; an α-helix

Full HSF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSF4 p.Ala320Gly Uncertain significance ★★ ⚠ same type
HSF4 p.Ala432Val Uncertain significance ★★ ⚠ same type
HSF4 p.Arg108Ser Uncertain significance ★★ ⚠ same type
HSF4 p.Glu115Gly Uncertain significance ★★ ⚠ same type
HSF4 p.Glu247= Uncertain significance ★★ same type
HSF4 p.Glu3Gly Uncertain significance ★★ ⚠ same type
HSF4 p.Gly13Asp Uncertain significance ★★ ⚠ same type
HSF4 p.Gly399Asp Uncertain significance ★★ ⚠ same type

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-ser52arg (accessed [today's date]).

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