Is HSD17B4 p.Pro4Arg (c.11C>G) pathogenic?

HSD17B4 p.Pro4Arg (c.11C>G) is classified Conflicting classifications of pathogenicity in HSD17B4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0812); Ultra-rare (popmax 0.0494%, sas); Associated with Inborn genetic diseases.

What condition is associated with HSD17B4 p.Pro4Arg (c.11C>G)?

HSD17B4 p.Pro4Arg (c.11C>G) is associated with Inborn genetic diseases, d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Pro4Arg (c.11C>G) in the general population?

HSD17B4 p.Pro4Arg (c.11C>G) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about HSD17B4 p.Pro4Arg (c.11C>G)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

HSD17B4 p.Pro4Arg

c.11C>G · rs142889209 · VCV504834

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -1.5
Regional constraint	o/e 1.10	unconstrained · MANE · 89 kb · p 0.0022 · regional, not allelic
Overall
CADD	11.9	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 0.0494% South Asian · 45/91,090 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.0279% 451/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
European (non-Finnish)	0.0333%	3,003
Remaining individualsnot grpmax-eligible	0.016%	6,250
Admixed American	0.00333%	30,011
African / African-American	0.00133%	75,046

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.Pro4Arg
Coding: c.11C>G
MANE Select: NM_000414
dbSNP: rs142889209
Type: single nucleotide variant
Location: chr5:119452586 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 4: the '(3r)-hydroxyacyl-coa dehydrogenase' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: d-bifunctional protein deficiency Perrault syndrome

Similar variants

HSD17B4 p.Pro4= Likely benign ★ 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-pro4arg (accessed [today's date]).

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