Is HPD p.Arg48fs (c.142del) pathogenic?

HPD p.Arg48fs (c.142del) is classified Pathogenic in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-03). Very rare (popmax 8.47e-05%, nfe); Associated with hawkinsinuria.

What condition is associated with HPD p.Arg48fs (c.142del)?

HPD p.Arg48fs (c.142del) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Arg48fs (c.142del) in the general population?

HPD p.Arg48fs (c.142del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hawkinsinuria inherited?

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

HPD p.Arg48fs

c.142del · rs2500327565 · VCV2950625

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

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 4 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.9	GERP -4.2

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.84e-05% 1/1,461,840 alleles · very 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: HPD
Protein: p.Arg48fs
Coding: c.142del
MANE Select: NM_002150
dbSNP: rs2500327565
Type: Deletion
Location: chr12:121857384 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 48: the voc 1 domain; a β-strand

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.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.Leu289fs Pathogenic ★ same condition
HPD p.Pro239fs Pathogenic ★ same condition
HPD c.31-33_31-11del Uncertain significance ★ same condition
HPD p.Arg119_Glu120delinsGln 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-arg48fs (accessed [today's date]).

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