Is HPD p.Leu289fs (c.865_866del) pathogenic?

HPD p.Leu289fs (c.865866del) is classified Pathogenic in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). No gnomAD frequency available for this variant; Associated with hawkinsinuria.

What condition is associated with HPD p.Leu289fs (c.865_866del)?

HPD p.Leu289fs (c.865_866del) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Leu289fs (c.865_866del) in the general population?

HPD p.Leu289fs (c.865_866del) is no gnomAD frequency available for this variant (gnomAD).

How is Hawkinsinuria inherited?

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

HPD p.Leu289fs

c.865_866del · rs2500289881 · VCV2948128

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hawkinsinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP -2.1, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HPD
Protein: p.Leu289fs
Coding: c.865_866del
MANE Select: NM_002150
dbSNP: rs2500289881
Type: Deletion
Location: chr12:121843798 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 289: a UniProt-annotated variant site (in tyrsn3; likely pathogenic); the voc 2 domain

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

Disease context

hawkinsinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tyrosinemia type III

For Hawkinsinuria (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

HPD p.Leu289= Likely benign ★ same residue
HPD p.Arg48fs Pathogenic ★ same condition
HPD p.Gln155fs Pathogenic ★ same condition
HPD p.Glu179fs Pathogenic ★ same condition
HPD p.Gly49fs Pathogenic ★ same condition
HPD p.Ile240fs Likely pathogenic ★ same condition
HPD p.Pro239fs Pathogenic ★ same condition
HPD c.31-33_31-11del 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/hpd-p-leu289fs (accessed [today's date]).

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