Is HSF4 p.Ser388fs (c.1162dup) pathogenic?

HSF4 p.Ser388fs (c.1162dup) is classified Uncertain significance in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). Very rare (popmax 0.000678%, nfe); Associated with cataract 5 multiple types.

What condition is associated with HSF4 p.Ser388fs (c.1162dup)?

HSF4 p.Ser388fs (c.1162dup) is associated with cataract 5 multiple types (ClinVar).

How common is HSF4 p.Ser388fs (c.1162dup) in the general population?

HSF4 p.Ser388fs (c.1162dup) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

HSF4 p.Ser388fs

c.1162dup · rs2145927381 · VCV1471650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

cataract 5 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,028 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,130 alleles · very rare exomes 8/1,461,818 · genomes 0/152,312 · 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.Ser388fs
Coding: c.1162dup
MANE Select: NM_001374675
dbSNP: rs2145927381
Type: Duplication
Location: chr16:67168907 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.04 · 2 PDB
Residue 388: 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

cataract 5 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

HSF4 p.Pro323fs Pathogenic ★★ same condition
HSF4 p.Gln180fs Pathogenic ★ same condition
HSF4 p.Glu425fs Pathogenic ★ same condition
HSF4 p.Ala145_Gln150dup Conflicting classifications of pathogenicity ★ same condition
HSF4 p.Ser388Asn Uncertain significance ★ ⚠ same residue
HSF4 p.Ala432Val Uncertain significance ★★ ⚠ same condition
HSF4 p.Arg108Ser Uncertain significance ★★ ⚠ same condition
HSF4 p.Glu115Gly 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-ser388fs (accessed [today's date]).

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