Is DPYS p.Arg475Ter (c.1423C>T) pathogenic?

DPYS p.Arg475Ter (c.1423C>T) is classified Pathogenic/Likely pathogenic in DPYS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0658%, mid); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Arg475Ter (c.1423C>T)?

DPYS p.Arg475Ter (c.1423C>T) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Arg475Ter (c.1423C>T) in the general population?

DPYS p.Arg475Ter (c.1423C>T) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

How is Dihydropyrimidinuria inherited?

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

DPYS p.Arg475Ter

c.1423C>T · rs61758444 · VCV446083

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 10
REVEL	0.048	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.1, phastCons 1
Overall
CADD	39.0	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 0.0658% Middle Eastern · 4/6,080 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0125% 201/1,613,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,520
Admixed American	0.0183%	5,453
European (non-Finnish)	0.0147%	6,821
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00267%	37,439
South Asian	0.0011%	91,072

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.Arg475Ter
Coding: c.1423C>T
MANE Select: NM_001385
dbSNP: rs61758444
Type: single nucleotide variant
Location: chr8:104392804 (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 475: 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.Arg475Gln Uncertain significance ★★ ⚠ 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.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-arg475ter (accessed [today's date]).

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