Is HPD p.Ser5Arg (c.15T>G) pathogenic?

HPD p.Ser5Arg (c.15T>G) is classified Benign in HPD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.3228); Common (popmax 5.76%, amr) — too common for a highly-penetrant pathogenic allele; Associated with hawkinsinuria.

What condition is associated with HPD p.Ser5Arg (c.15T>G)?

HPD p.Ser5Arg (c.15T>G) 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.

What do computational predictors say about HPD p.Ser5Arg (c.15T>G)?

AlphaMissense predicts likely benign (score 0.3228) — an in-silico prediction, not a clinical call.

HPD p.Ser5Arg

Q: How common is HPD p.Ser5Arg (c.15T>G) in the general population?

HPD p.Ser5Arg (c.15T>G) is common (popmax 5.76%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.15T>G · rs35849100 · VCV235261

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3228 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.76%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hawkinsinuria

Computational evidence

Protein change
AlphaMissense	0.3228	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4	GERP -3.9
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	16.64	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 5.76% Admixed American · 3,458/60,006 alleles

Filtering AF 5.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.54%

Overall 0.6% 9,678/1,613,958 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.76%	17
South Asian	0.96%	104
Middle Eastern	0.759%	132
Remaining individualsnot grpmax-eligible	0.558%	179
Amishnot grpmax-eligible	0.44%	228
European (non-Finnish)	0.398%	251
Ashkenazi Jewishnot grpmax-eligible	0.213%	470
Finnishnot grpmax-eligible	0.155%	647
African / African-American	0.113%	882
East Asian	0.0134%	7,478

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.Ser5Arg
Coding: c.15T>G
dbSNP: rs35849100
Type: single nucleotide variant
Location: chr12:121858702 (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-ser5arg (accessed [today's date]).

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