Is HSF4 p.Arg405= (c.1213C>A) pathogenic?

HSF4 p.Arg405= (c.1213C>A) is classified Likely benign in HSF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-10-19). Very rare (popmax 0.00223%, eas); Associated with HSF4-related disorder.

What condition is associated with HSF4 p.Arg405= (c.1213C>A)?

HSF4 p.Arg405= (c.1213C>A) is associated with HSF4-related disorder (ClinVar).

How common is HSF4 p.Arg405= (c.1213C>A) in the general population?

HSF4 p.Arg405= (c.1213C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

HSF4 p.Arg405=

c.1213C>A · rs761738142 · VCV3032590

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

HSF4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.028	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.33	GERP -3.5, phastCons 0.26
Overall
CADD	8.465	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,718 alleles · very rare exomes 5/1,461,516 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	0.000339%	295,004

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.Arg405=
Coding: c.1213C>A
MANE Select: NM_001374675
dbSNP: rs761738142
Type: single nucleotide variant
Location: chr16:67169060 (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

HSF4-related disorder

Similar variants

HSF4 p.Arg405Ter Pathogenic ★ same residue
HSF4 p.Arg119Cys Pathogenic ★ same condition
HSF4 p.Gln112Ter Likely pathogenic ★ same condition
HSF4 p.Glu3Ter Likely pathogenic ★ same condition
HSF4 c.562-1G>C Uncertain significance ★ same condition
HSF4 p.Leu136Val Uncertain significance ★ ⚠ same condition
HSF4 p.Arg118Gly Uncertain significance ⚠ same condition
HSF4 p.Tyr78Ser 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-arg405 (accessed [today's date]).

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