Is HPD p.Pro339= (c.1017G>A) pathogenic?

HPD p.Pro339= (c.1017G>A) is classified Likely benign in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). Very rare (popmax 0.00203%, nfe); Associated with hawkinsinuria.

What condition is associated with HPD p.Pro339= (c.1017G>A)?

HPD p.Pro339= (c.1017G>A) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Pro339= (c.1017G>A) in the general population?

HPD p.Pro339= (c.1017G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

How is Hawkinsinuria inherited?

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

HPD p.Pro339=

c.1017G>A · rs750266795 · VCV2929801

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

hawkinsinuria

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 0.36	GERP -3.9, phastCons 0.3
Overall
CADD	9.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,962 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00149% 24/1,613,808 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.Pro339=
Coding: c.1017G>A
MANE Select: NM_002150
dbSNP: rs750266795
Type: single nucleotide variant
Location: chr12:121839986 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 339: a UniProt-annotated variant site (in tyrsn3; likely pathogenic)

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.Pro339Arg Uncertain significance ★ ⚠ same residue
HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Gln205Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Tyr160Cys Likely pathogenic ★★ same condition
HPD p.Ala230Thr Uncertain significance ★★ ⚠ same condition
HPD p.Arg111Trp Uncertain significance ★★ ⚠ same condition
HPD p.Arg119Gln Uncertain significance ★★ ⚠ same condition
HPD p.Arg279Gly 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-pro339 (accessed [today's date]).

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