Is HSD17B4 p.Lys681Glu (c.2041A>G) pathogenic?

HSD17B4 p.Lys681Glu (c.2041A>G) is classified Conflicting classifications of pathogenicity in HSD17B4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0587); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with HSD17B4 p.Lys681Glu (c.2041A>G)?

HSD17B4 p.Lys681Glu (c.2041A>G) is associated with Inborn genetic diseases, d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Lys681Glu (c.2041A>G) in the general population?

HSD17B4 p.Lys681Glu (c.2041A>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about HSD17B4 p.Lys681Glu (c.2041A>G)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

HSD17B4 p.Lys681Glu

c.2041A>G · rs139348491 · VCV594879

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -6.51	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 2.2	GERP -0.73, phastCons 0.6
Regional constraint	o/e 1.10	unconstrained · MANE · 89 kb · p 0.0022 · regional, not allelic
Overall
CADD	13.14	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 0.0227% African / African-American · 17/74,986 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00149% 24/1,612,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,411
Admixed American	0.00334%	29,935
Remaining individualsnot grpmax-eligible	0.0016%	62,414
European (non-Finnish)	0.000339%	294,687

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.Lys681Glu
Coding: c.2041A>G
MANE Select: NM_000414
dbSNP: rs139348491
Type: single nucleotide variant
Location: chr5:119536470 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 681: the scp2 domain

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 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
HSD17B4 c.1993+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-lys681glu (accessed [today's date]).

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