Is HSF1 p.Ser403Arg (c.1209C>A) pathogenic?

HSF1 p.Ser403Arg (c.1209C>A) is classified Uncertain significance in HSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: ambiguous (0.5273); Absent from gnomAD v4.1.

How common is HSF1 p.Ser403Arg (c.1209C>A) in the general population?

HSF1 p.Ser403Arg (c.1209C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HSF1 p.Ser403Arg (c.1209C>A)?

AlphaMissense predicts ambiguous (score 0.5273) — an in-silico prediction, not a clinical call.

HSF1 p.Ser403Arg

c.1209C>A · rs553532407 · VCV3107195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5273 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5273	ambiguous
REVEL	0.05	moderately benign-leaning
SaProt	LLR -8.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.6	GERP -3.3
Regional constraint	o/e 1.18	unconstrained · MANE · 2,736 bp · p 0.00036 · regional, not allelic
Overall
CADD	2.468	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: HSF1
Protein: p.Ser403Arg
Coding: c.1209C>A
MANE Select: NM_005526
dbSNP: rs553532407
Type: single nucleotide variant
Location: chr8:144313577 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.61 · 8 PDB
Residue 403: the 'transactivation domain' region; the 'hydrophobic repeat hr-c' region

Full HSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSF1 p.Asp143= Benign ★★ same type
HSF1 p.Thr24= Benign ★★ same type
HSF1 p.Ala160Thr Uncertain significance ★ ⚠ same type
HSF1 p.Ala173Thr Uncertain significance ★ ⚠ same type
HSF1 p.Ala313Glu Uncertain significance ★ ⚠ same type
HSF1 p.Ala343Thr Uncertain significance ★ ⚠ same type
HSF1 p.Ala437Thr Uncertain significance ★ ⚠ same type
HSF1 p.Ala470Glu 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/hsf1-p-ser403arg (accessed [today's date]).

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