Is DPYD p.Ser780fs (c.2338_2339del) pathogenic?

DPYD p.Ser780fs (c.23382339del) is classified Likely pathogenic in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-25). Very rare (popmax 0.0011%, nfe); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Ser780fs (c.2338_2339del)?

DPYD p.Ser780fs (c.2338_2339del) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Ser780fs (c.2338_2339del) in the general population?

DPYD p.Ser780fs (c.2338_2339del) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

DPYD p.Ser780fs

c.2338_2339del · rs1162905063 · VCV2674910

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

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 19 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP -0.72, 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 0.0011% European (non-Finnish) · 13/1,180,000 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,613,970 alleles · very rare

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.Ser780fs
Coding: c.2338_2339del
MANE Select: NM_000110
dbSNP: rs1162905063
Type: Deletion
Location: chr1:97234955 (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-ser780fs (accessed [today's date]).

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