Is HSD17B4 p.Phe377= (c.1131C>T) pathogenic?

HSD17B4 p.Phe377= (c.1131C>T) is classified Conflicting classifications of pathogenicity in HSD17B4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0703%, sas); Associated with Perrault syndrome.

What condition is associated with HSD17B4 p.Phe377= (c.1131C>T)?

HSD17B4 p.Phe377= (c.1131C>T) is associated with Perrault syndrome, Perrault syndrome 1, d-bifunctional protein deficiency (ClinVar).

How common is HSD17B4 p.Phe377= (c.1131C>T) in the general population?

HSD17B4 p.Phe377= (c.1131C>T) is ultra-rare (popmax 0.0703%, sas) (gnomAD).

How is Perrault syndrome inherited?

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

HSD17B4 p.Phe377=

c.1131C>T · rs200347945 · VCV350465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, sas)

Conditions

Perrault syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -3.6, phastCons 0.002
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% South Asian · 64/91,078 alleles

Filtering AF 0.0565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00725% 117/1,613,692 alleles · ultra-rare exomes 108/1,461,550 · genomes 9/152,142 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0703%	1,423
Remaining individualsnot grpmax-eligible	0.0432%	2,314
Admixed American	0.0117%	8,570
East Asian	0.00892%	11,212
African / African-American	0.004%	24,996
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.000932%	107,251

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.Phe377=
Coding: c.1131C>T
MANE Select: NM_000414
dbSNP: rs200347945
Type: single nucleotide variant
Location: chr5:119499475 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 377: an α-helix; 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: Perrault syndrome 1 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.1333+1G>C 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-phe377 (accessed [today's date]).

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