Is HSF4 p.Leu91= (c.271C>T) pathogenic?

HSF4 p.Leu91= (c.271C>T) is classified Likely benign in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-17). Very rare (popmax 8.48e-05%, nfe).

How common is HSF4 p.Leu91= (c.271C>T) in the general population?

HSF4 p.Leu91= (c.271C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

HSF4 p.Leu91=

c.271C>T · VCV4930418

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Overall
CADD	15.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,768 alleles

Overall 6.21e-05% 1/1,611,318 alleles · very rare exomes 1/1,459,010 · genomes 0/152,308 · joint denominator

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.Leu91=
Coding: c.271C>T
MANE Select: NM_001374675
Type: single nucleotide variant
Location: chr16:67165757 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 91: a DNA-binding region

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-leu91 (accessed [today's date]).

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