Is HPD p.Thr138= (c.414G>A) pathogenic?

HPD p.Thr138= (c.414G>A) is classified Benign/Likely benign in HPD (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele; Associated with hawkinsinuria.

What condition is associated with HPD p.Thr138= (c.414G>A)?

HPD p.Thr138= (c.414G>A) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How is Hawkinsinuria inherited?

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

HPD p.Thr138=

Q: How common is HPD p.Thr138= (c.414G>A) in the general population?

HPD p.Thr138= (c.414G>A) is common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.414G>A · rs140788110 · VCV307485

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 7.35%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

hawkinsinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.12	GERP 1.6, phastCons 0.92
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.35% Admixed American · 4,410/59,998 alleles

Filtering AF 7.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1%

Overall 0.314% 5,053/1,610,788 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	7.35%	14
East Asian	0.312%	320
Remaining individualsnot grpmax-eligible	0.282%	354
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
African / African-American	0.0774%	1,293
South Asian	0.0286%	3,500
European (non-Finnish)	0.0178%	5,605
Finnishnot grpmax-eligible	0.00156%	64,024

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.Thr138=
Coding: c.414G>A
MANE Select: NM_002150
dbSNP: rs140788110
Type: single nucleotide variant
Location: chr12:121854703 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 138: the voc 1 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.Thr138Met Uncertain significance ★ ⚠ same residue
HPD p.Thr138del 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

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-thr138 (accessed [today's date]).

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