Is HSD17B4 p.Ser522Arg (c.1566T>A) pathogenic?

HSD17B4 p.Ser522Arg (c.1566T>A) is classified Conflicting classifications of pathogenicity in HSD17B4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1673); Rare (popmax 0.243%, eas); Associated with Perrault syndrome.

What condition is associated with HSD17B4 p.Ser522Arg (c.1566T>A)?

HSD17B4 p.Ser522Arg (c.1566T>A) is associated with Perrault syndrome, Perrault syndrome 1, d-bifunctional protein deficiency (ClinVar).

How common is HSD17B4 p.Ser522Arg (c.1566T>A) in the general population?

HSD17B4 p.Ser522Arg (c.1566T>A) is rare (popmax 0.243%, eas) (gnomAD).

How is Perrault syndrome inherited?

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

What do computational predictors say about HSD17B4 p.Ser522Arg (c.1566T>A)?

AlphaMissense predicts likely benign (score 0.1673) — an in-silico prediction, not a clinical call.

HSD17B4 p.Ser522Arg

c.1566T>A · rs184492796 · VCV226666

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1673 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.243%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Perrault syndrome

Computational evidence

Protein change
AlphaMissense	0.1673	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP -2.5
Regional constraint	o/e 1.10	unconstrained · MANE · 89 kb · p 0.0022 · regional, not allelic
Overall
CADD	15.17	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 0.243% East Asian · 109/44,804 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.192%

Overall 0.00791% 127/1,604,996 alleles · rare exomes 114/1,452,712 · genomes 13/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.243%	411
Remaining individualsnot grpmax-eligible	0.0241%	4,143
Admixed American	0.00167%	59,898
South Asian	0.0011%	90,902
European (non-Finnish)	8.53e-05%	1,172,005

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.Ser522Arg
Coding: c.1566T>A
MANE Select: NM_000414
dbSNP: rs184492796
Type: single nucleotide variant
Location: chr5:119525278 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 522: 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

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-ser522arg (accessed [today's date]).

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