Is HPD p.Arg378Pro (c.1133G>C) pathogenic?

HPD p.Arg378Pro (c.1133G>C) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-24). AlphaMissense: likely pathogenic (0.9884); Very rare (popmax 0.00133%, afr); Associated with tyrosinemia type III.

What condition is associated with HPD p.Arg378Pro (c.1133G>C)?

HPD p.Arg378Pro (c.1133G>C) is associated with tyrosinemia type III, hawkinsinuria (ClinVar).

How common is HPD p.Arg378Pro (c.1133G>C) in the general population?

HPD p.Arg378Pro (c.1133G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Tyrosinemia type 3 inherited?

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

What do computational predictors say about HPD p.Arg378Pro (c.1133G>C)?

AlphaMissense predicts likely pathogenic (score 0.9884) — an in-silico prediction, not a clinical call.

HPD p.Arg378Pro

c.1133G>C · rs560715209 · VCV1423977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type III

Computational evidence

Protein change
AlphaMissense	0.9884	likely pathogenic · top 3% in HPD
REVEL	0.748	pathogenic-leaning
SaProt	LLR -18.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	26.8	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

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Overall 0.000124% 2/1,614,182 alleles · very rare exomes 1/1,461,868 · genomes 1/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,048
European (non-Finnish)	8.47e-05%	1,180,012

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.Arg378Pro
Coding: c.1133G>C
MANE Select: NM_002150
dbSNP: rs560715209
Type: single nucleotide variant
Location: chr12:121839777 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 378: a UniProt-annotated variant site (in tyrsn3; likely pathogenic)

Full HPD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tyrosinemia type III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hawkinsinuria

For Tyrosinemia type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HPD p.Arg378= Likely benign ★ 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
HPD p.Arg279Gly 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-arg378pro (accessed [today's date]).

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