Is HPD p.Ile153= (c.459C>T) pathogenic?

HPD p.Ile153= (c.459C>T) is classified Likely benign in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). Ultra-rare (popmax 0.015%, amr); Associated with hawkinsinuria.

What condition is associated with HPD p.Ile153= (c.459C>T)?

HPD p.Ile153= (c.459C>T) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Ile153= (c.459C>T) in the general population?

HPD p.Ile153= (c.459C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is Hawkinsinuria inherited?

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

HPD p.Ile153=

c.459C>T · rs776490022 · VCV2926175

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

hawkinsinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -3.9
Overall
CADD	0.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,982 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00558% 90/1,613,784 alleles · ultra-rare exomes 85/1,461,686 · genomes 5/152,098 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,665
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.0061%	16,388
East Asian	0.00446%	22,445
African / African-American	0.00267%	37,438
South Asian	0.0011%	91,084

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.Ile153=
Coding: c.459C>T
MANE Select: NM_002150
dbSNP: rs776490022
Type: single nucleotide variant
Location: chr12:121849746 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB

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.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
HPD p.Arg300Trp 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-ile153 (accessed [today's date]).

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