Is HPD p.Phe133Ser (c.398T>C) pathogenic?

HPD p.Phe133Ser (c.398T>C) is classified Conflicting classifications of pathogenicity in HPD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.5826); Rare (popmax 0.242%, sas); Associated with hawkinsinuria.

What condition is associated with HPD p.Phe133Ser (c.398T>C)?

HPD p.Phe133Ser (c.398T>C) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Phe133Ser (c.398T>C) in the general population?

HPD p.Phe133Ser (c.398T>C) is rare (popmax 0.242%, sas) (gnomAD).

How is Hawkinsinuria inherited?

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

What do computational predictors say about HPD p.Phe133Ser (c.398T>C)?

AlphaMissense predicts likely pathogenic (score 0.5826) — an in-silico prediction, not a clinical call.

HPD p.Phe133Ser

c.398T>C · rs545913399 · VCV2049011

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5826 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.242%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hawkinsinuria

Computational evidence

Protein change
AlphaMissense	0.5826	likely pathogenic
REVEL	0.329	indeterminate
SaProt	LLR -11.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.242% South Asian · 220/91,076 alleles

Filtering AF 0.215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.205%

Overall 0.0145% 234/1,613,774 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.242%	414
Remaining individualsnot grpmax-eligible	0.0112%	8,928
East Asian	0.00446%	22,436
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000339%	294,927

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.Phe133Ser
Coding: c.398T>C
MANE Select: NM_002150
dbSNP: rs545913399
Type: single nucleotide variant
Location: chr12:121854719 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 133: 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.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-phe133ser (accessed [today's date]).

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