Is HSD17B4 p.Ser554Pro (c.1660T>C) pathogenic?

HSD17B4 p.Ser554Pro (c.1660T>C) is classified Uncertain significance in HSD17B4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-27). AlphaMissense: likely benign (0.2359); Ultra-rare (popmax 0.0301%, amr); Associated with d-bifunctional protein deficiency.

What condition is associated with HSD17B4 p.Ser554Pro (c.1660T>C)?

HSD17B4 p.Ser554Pro (c.1660T>C) is associated with d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Ser554Pro (c.1660T>C) in the general population?

HSD17B4 p.Ser554Pro (c.1660T>C) is ultra-rare (popmax 0.0301%, amr) (gnomAD).

How is Bifunctional enzyme deficiency inherited?

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

What do computational predictors say about HSD17B4 p.Ser554Pro (c.1660T>C)?

AlphaMissense predicts likely benign (score 0.2359) — an in-silico prediction, not a clinical call.

HSD17B4 p.Ser554Pro

c.1660T>C · rs199659543 · VCV944666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2359 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0301%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

d-bifunctional protein deficiency

Computational evidence

Protein change
AlphaMissense	0.2359	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.9, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 89 kb · p 0.0022 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0301% Admixed American · 18/59,888 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00326% 52/1,594,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0301%	3,327
Remaining individualsnot grpmax-eligible	0.00971%	10,302
European (non-Finnish)	0.00241%	41,525

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.Ser554Pro
Coding: c.1660T>C
MANE Select: NM_000414
dbSNP: rs199659543
Type: single nucleotide variant
Location: chr5:119526003 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 554: an α-helix; 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

Also linked: Perrault syndrome

For Bifunctional enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

HSD17B4 p.Ser554fs Likely pathogenic ★ 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
HSD17B4 c.1768-1G>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-ser554pro (accessed [today's date]).

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