Is DPYS p.Gln478Pro (c.1433A>C) pathogenic?

DPYS p.Gln478Pro (c.1433A>C) is classified Uncertain significance in DPYS (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: ambiguous (0.4592); Very rare (popmax 0.000678%, nfe); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Gln478Pro (c.1433A>C)?

DPYS p.Gln478Pro (c.1433A>C) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Gln478Pro (c.1433A>C) in the general population?

DPYS p.Gln478Pro (c.1433A>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is Dihydropyrimidinuria inherited?

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

What do computational predictors say about DPYS p.Gln478Pro (c.1433A>C)?

AlphaMissense predicts ambiguous (score 0.4592) — an in-silico prediction, not a clinical call.

DPYS p.Gln478Pro

c.1433A>C · rs765274405 · VCV909730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
AlphaMissense	0.4592	ambiguous
REVEL	0.623	indeterminate
SaProt	LLR -10.79	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	24.1	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 0.000678% European (non-Finnish) · 8/1,180,024 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,058 alleles · very rare

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: DPYS
Protein: p.Gln478Pro
Coding: c.1433A>C
MANE Select: NM_001385
dbSNP: rs765274405
Type: single nucleotide variant
Location: chr8:104392794 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB
Residue 478: an α-helix

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

Disease context

dihydropyrimidinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dihydropyrimidinuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

DPYS p.Arg302Gln Likely pathogenic ★★ same condition
DPYS p.Arg302Ter Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg465Ter Pathogenic ★★ same condition
DPYS p.Arg475Ter Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg490Cys Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg490His Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Gln190Ter Pathogenic ★★ same condition
DPYS p.Gln334Arg Pathogenic ★★ 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/dpys-p-gln478pro (accessed [today's date]).

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