Is DPYS p.Ala255= (c.765T>C) pathogenic?

DPYS p.Ala255= (c.765T>C) is classified Benign in DPYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-20). Low-frequency (popmax 1.46%, afr); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Ala255= (c.765T>C)?

DPYS p.Ala255= (c.765T>C) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Ala255= (c.765T>C) in the general population?

DPYS p.Ala255= (c.765T>C) is low-frequency (popmax 1.46%, afr) (gnomAD).

How is Dihydropyrimidinuria inherited?

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

DPYS p.Ala255=

c.765T>C · rs35371065 · VCV100141

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.46%, afr)

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.6	GERP -3.9
Overall
CADD	1.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.46% African / African-American · 1,096/75,070 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.36%

Overall 0.0778% 1,256/1,614,232 alleles · low-frequency exomes 653/1,461,878 · genomes 603/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.46%	68
Middle Eastern	0.132%	758
Remaining individualsnot grpmax-eligible	0.117%	856
Admixed American	0.0816%	1,225
South Asian	0.00549%	18,218
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00203%	49,169

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.Ala255=
Coding: c.765T>C
MANE Select: NM_001385
dbSNP: rs35371065
Type: single nucleotide variant
Location: chr8:104444276 (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 255: 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-ala255 (accessed [today's date]).

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