Is HSD17B4 p.Ala71= (c.213C>T) pathogenic?

HSD17B4 p.Ala71= (c.213C>T) is classified Likely benign in HSD17B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-20). Very rare (popmax 0.00027%, nfe); Associated with d-bifunctional protein deficiency.

What condition is associated with HSD17B4 p.Ala71= (c.213C>T)?

HSD17B4 p.Ala71= (c.213C>T) is associated with d-bifunctional protein deficiency, Perrault syndrome (ClinVar).

How common is HSD17B4 p.Ala71= (c.213C>T) in the general population?

HSD17B4 p.Ala71= (c.213C>T) is very rare (popmax 0.00027%, nfe) (gnomAD).

How is Bifunctional enzyme deficiency inherited?

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

HSD17B4 p.Ala71=

c.213C>T · rs1002700026 · VCV2929052

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00027%, nfe)

Conditions

d-bifunctional protein deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.5, phastCons 1
Overall
CADD	13.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00027% European (non-Finnish) · 3/1,112,256 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000288% 4/1,386,616 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00167%	59,904
European (non-Finnish)grpmax	0.00027%	370,752

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala71=
Coding: c.213C>T
MANE Select: NM_000414
dbSNP: rs1002700026
Type: single nucleotide variant
Location: chr5:119474008 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 7 PDB
Residue 71: the '(3r)-hydroxyacyl-coa dehydrogenase' region; a β-strand

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

Disease context

d-bifunctional protein deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Perrault syndrome

For Bifunctional enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

HSD17B4 p.Ala71fs Likely pathogenic ★ 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-ala71 (accessed [today's date]).

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