Is DPYS p.Arg490Cys (c.1468C>T) pathogenic?

DPYS p.Arg490Cys (c.1468C>T) is classified Pathogenic/Likely pathogenic in DPYS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-22). AlphaMissense: likely pathogenic (0.7926); Rare (popmax 0.1%, eas); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Arg490Cys (c.1468C>T)?

DPYS p.Arg490Cys (c.1468C>T) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Arg490Cys (c.1468C>T) in the general population?

DPYS p.Arg490Cys (c.1468C>T) is rare (popmax 0.1%, eas) (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.Arg490Cys (c.1468C>T)?

AlphaMissense predicts likely pathogenic (score 0.7926) — an in-silico prediction, not a clinical call.

DPYS p.Arg490Cys

c.1468C>T · rs142574766 · VCV1029334

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7926 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
AlphaMissense	0.7926	likely pathogenic ✓ concordant with ClinVar
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -13.64	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 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	27.6	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 0.1% East Asian · 45/44,876 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00483% 78/1,614,062 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	997
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,834
South Asian	0.00329%	30,361
African / African-American	0.00267%	37,511
European (non-Finnish)	0.00195%	51,303
Admixed American	0.00167%	60,024

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.Arg490Cys
Coding: c.1468C>T
MANE Select: NM_001385
dbSNP: rs142574766
Type: single nucleotide variant
Location: chr8:104381290 (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 490: a UniProt-annotated variant site (in dpysd)

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.Arg490His Pathogenic/Likely pathogenic ★★ same residue
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.Gln190Ter Pathogenic ★★ same condition
DPYS p.Gln334Arg Pathogenic ★★ same condition
DPYS p.Gln85Ter Pathogenic/Likely 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-arg490cys (accessed [today's date]).

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