Is HSD17B4 p.Val445= (c.1335C>A) pathogenic?

HSD17B4 p.Val445= (c.1335C>A) is classified Likely benign in HSD17B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). Very rare (popmax 0.00531%, nfe); Associated with Perrault syndrome.

What condition is associated with HSD17B4 p.Val445= (c.1335C>A)?

HSD17B4 p.Val445= (c.1335C>A) is associated with Perrault syndrome, d-bifunctional protein deficiency (ClinVar).

How common is HSD17B4 p.Val445= (c.1335C>A) in the general population?

HSD17B4 p.Val445= (c.1335C>A) is very rare (popmax 0.00531%, nfe) (gnomAD).

How is Perrault syndrome inherited?

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

HSD17B4 p.Val445=

c.1335C>A · rs749383778 · VCV799063

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00531%, nfe)

Conditions

Perrault syndrome

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 -1.7	GERP -2.1
Overall
CADD	2.408	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00531% European (non-Finnish) · 57/1,073,970 alleles

Filtering AF 0.00415% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00379%

Overall 0.00401% 60/1,497,194 alleles · very rare exomes 57/1,345,134 · genomes 3/152,060 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00531%	18,842
Remaining individualsnot grpmax-eligible	0.00512%	19,550

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: HSD17B4
Protein: p.Val445=
Coding: c.1335C>A
MANE Select: NM_000414
dbSNP: rs749383778
Type: single nucleotide variant
Location: chr5:119509142 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 445: a β-strand; the 'enoyl-coa hydratase 2' region

Full HSD17B4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Perrault syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: d-bifunctional protein deficiency

For Perrault syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

HSD17B4 c.1210-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1262-1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1438-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1503+1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1573+1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1574-1G>A Likely pathogenic ★★ same condition
HSD17B4 c.1768-1G>A Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.1993+1G>A Pathogenic/Likely pathogenic ★★ 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/hsd17b4-p-val445 (accessed [today's date]).

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