Is HSD17B4 p.Pro489Ser (c.1465C>T) pathogenic?

HSD17B4 p.Pro489Ser (c.1465C>T) is classified Uncertain significance in HSD17B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.3315); Ultra-rare (popmax 0.0122%, sas); Associated with Inborn genetic diseases.

What condition is associated with HSD17B4 p.Pro489Ser (c.1465C>T)?

HSD17B4 p.Pro489Ser (c.1465C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HSD17B4 p.Pro489Ser (c.1465C>T) in the general population?

HSD17B4 p.Pro489Ser (c.1465C>T) is ultra-rare (popmax 0.0122%, sas) (gnomAD).

What do computational predictors say about HSD17B4 p.Pro489Ser (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.3315) — an in-silico prediction, not a clinical call.

HSD17B4 p.Pro489Ser

c.1465C>T · rs761868163 · VCV2616369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3315	likely benign
REVEL	0.668	pathogenic-leaning
SaProt	LLR -10.33	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 89 kb · p 0.0022 · regional, not allelic
Overall
CADD	25.3	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 0.0122% South Asian · 11/90,428 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.000694% 11/1,584,576 alleles · ultra-rare

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.Pro489Ser
Coding: c.1465C>T
MANE Select: NM_000414
dbSNP: rs761868163
Type: single nucleotide variant
Location: chr5:119515008 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 489: 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

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

Similar variants

HSD17B4 p.Leu236Ter Pathogenic ★★ same condition
HSD17B4 p.Ala54Asp Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Ala561Ser Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Arg106Cys Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Arg555Gly Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Arg633His Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Arg634Cys Uncertain significance ★★ ⚠ same condition
HSD17B4 p.Asp495Gly Uncertain significance ★★ ⚠ 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-pro489ser (accessed [today's date]).

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