Is HPD p.Phe35Ser (c.104T>C) pathogenic?

HPD p.Phe35Ser (c.104T>C) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-26). AlphaMissense: likely pathogenic (0.7246); No allele count reported in gnomAD v4.1 (AN 1,611,864); Associated with hawkinsinuria.

What condition is associated with HPD p.Phe35Ser (c.104T>C)?

HPD p.Phe35Ser (c.104T>C) is associated with hawkinsinuria, tyrosinemia type III (ClinVar).

How common is HPD p.Phe35Ser (c.104T>C) in the general population?

HPD p.Phe35Ser (c.104T>C) is no allele count reported in gnomAD v4.1 (AN 1,611,864) (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.Phe35Ser (c.104T>C)?

AlphaMissense predicts likely pathogenic (score 0.7246) — an in-silico prediction, not a clinical call.

HPD p.Phe35Ser

c.104T>C · rs1592923946 · VCV638896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7246 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,864)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hawkinsinuria

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.7246	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -10.53	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.9	GERP -1.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,611,864). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HPD
Protein: p.Phe35Ser
Coding: c.104T>C
MANE Select: NM_002150
dbSNP: rs1592923946
Type: single nucleotide variant
Location: chr12:121857422 (GRCh38)

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)

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-phe35ser (accessed [today's date]).

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