Is DPYS p.Arg503fs (c.1506del) pathogenic?

DPYS p.Arg503fs (c.1506del) is classified Conflicting classifications of pathogenicity in DPYS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-09-30). Rare (popmax 0.272%, afr); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Arg503fs (c.1506del)?

DPYS p.Arg503fs (c.1506del) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Arg503fs (c.1506del) in the general population?

DPYS p.Arg503fs (c.1506del) is rare (popmax 0.272%, afr) (gnomAD).

How is Dihydropyrimidinuria inherited?

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

DPYS p.Arg503fs

c.1506del · rs79080341 · VCV100132

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.272%, afr)

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.38	GERP 0.47
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.272% African / African-American · 204/75,060 alleles

Filtering AF 0.241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.229%

Overall 0.0154% 248/1,614,204 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.272%	368
Middle Eastern	0.0495%	2,021
Admixed American	0.0383%	2,610
Remaining individualsnot grpmax-eligible	0.0192%	5,209
South Asian	0.00439%	22,770
European (non-Finnish)	0.000169%	590,012

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: DPYS
Protein: p.Arg503fs
Coding: c.1506del
MANE Select: NM_001385
dbSNP: rs79080341
Type: Deletion
Location: chr8:104381252 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB

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 c.1092+5del Likely pathogenic ★★ same condition
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

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-arg503fs (accessed [today's date]).

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