Is DPYD p.Trp459fs (c.1375_1388del) pathogenic?

DPYD p.Trp459fs (c.13751388del) is classified Likely pathogenic in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-30). Ultra-rare (popmax 0.011%, sas); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Trp459fs (c.1375_1388del)?

DPYD p.Trp459fs (c.1375_1388del) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Trp459fs (c.1375_1388del) in the general population?

DPYD p.Trp459fs (c.1375_1388del) is ultra-rare (popmax 0.011%, sas) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

DPYD p.Trp459fs

c.1375_1388del · rs757940841 · VCV2674906

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

dihydropyrimidine dehydrogenase deficiency

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 12 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -2.3, phastCons 1
Overall
CADD	35.0	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 0.011% South Asian · 10/91,082 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000682% 11/1,613,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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: DPYD
Protein: p.Trp459fs
Coding: c.1375_1388del
MANE Select: NM_000110
dbSNP: rs757940841
Type: Deletion
Location: chr1:97549696 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23

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

Disease context

dihydropyrimidine dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dihydropyrimidine dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

DPYD c.1977_1983del Likely pathogenic ★★ same condition
DPYD p.Arg589fs Likely pathogenic ★★ same condition
DPYD p.Arg916fs Likely pathogenic ★★ same condition
DPYD p.Gln860fs Pathogenic/Likely pathogenic ★★ same condition
DPYD p.Leu682fs Likely pathogenic ★★ same condition
DPYD p.Lys42_Arg43insTer Pathogenic/Likely pathogenic ★★ same condition
DPYD c.850+23455_1128+8811del Likely pathogenic ★ same condition
DPYD p.Ala946fs 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/dpyd-p-trp459fs (accessed [today's date]).

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