Is HSD17B4 p.Arg199= (c.597G>A) pathogenic?

HSD17B4 p.Arg199= (c.597G>A) is classified Likely benign in HSD17B4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-08). Very rare (popmax 0.00267%, afr); Associated with d-bifunctional protein deficiency.

What condition is associated with HSD17B4 p.Arg199= (c.597G>A)?

HSD17B4 p.Arg199= (c.597G>A) is associated with d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Arg199= (c.597G>A) in the general population?

HSD17B4 p.Arg199= (c.597G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Bifunctional enzyme deficiency inherited?

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

HSD17B4 p.Arg199=

c.597G>A · rs770261826 · VCV668261

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

d-bifunctional protein deficiency

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 0.011	GERP -1.4
Overall
CADD	8.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,998 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00198% 29/1,461,246 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,499
European (non-Finnish)	0.0022%	45,368
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Arg199=
Coding: c.597G>A
MANE Select: NM_000414
dbSNP: rs770261826
Type: single nucleotide variant
Location: chr5:119478996 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 199: a binding site; the '(3r)-hydroxyacyl-coa dehydrogenase' region; a turn

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

Also linked: Perrault syndrome

For Bifunctional enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

HSD17B4 p.Arg199Gln Uncertain significance ★ ⚠ same residue
HSD17B4 p.Arg199Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg199 (accessed [today's date]).

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