Is HSD17B4 p.Leu499fs (c.1496_1497del) pathogenic?

HSD17B4 p.Leu499fs (c.14961497del) is classified Likely pathogenic in HSD17B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). No gnomAD frequency available for this variant; Associated with d-bifunctional protein deficiency.

What condition is associated with HSD17B4 p.Leu499fs (c.1496_1497del)?

HSD17B4 p.Leu499fs (c.1496_1497del) is associated with d-bifunctional protein deficiency (ClinVar).

How common is HSD17B4 p.Leu499fs (c.1496_1497del) in the general population?

HSD17B4 p.Leu499fs (c.1496_1497del) is no gnomAD frequency available for this variant (gnomAD).

How is Bifunctional enzyme deficiency inherited?

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

HSD17B4 p.Leu499fs

c.1496_1497del · rs2531841219 · VCV1724489

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

d-bifunctional protein deficiency

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 17 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 0.92

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HSD17B4
Protein: p.Leu499fs
Coding: c.1496_1497del
MANE Select: NM_000414
dbSNP: rs2531841219
Type: Deletion
Location: chr5:119515039 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 499: the maoc-like domain; the 'enoyl-coa hydratase 2' region

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

Disease context

d-bifunctional protein deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bifunctional enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

HSD17B4 p.Leu499Arg Uncertain significance ★ ⚠ same residue
HSD17B4 c.302+3_302+6del Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 c.868+1del Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 p.Asp115fs Pathogenic ★★ same condition
HSD17B4 p.Cys373fs Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 p.His312_Thr313insTer Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 p.Phe90fs Pathogenic/Likely pathogenic ★★ same condition
HSD17B4 p.Pro263fs 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-leu499fs (accessed [today's date]).

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