Is DPYD p.Phe100fs (c.299_302del) pathogenic?

DPYD p.Phe100fs (c.299302del) is classified Pathogenic in DPYD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.0148%, nfe); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Phe100fs (c.299_302del)?

DPYD p.Phe100fs (c.299_302del) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Phe100fs (c.299_302del) in the general population?

DPYD p.Phe100fs (c.299_302del) is ultra-rare (popmax 0.0148%, nfe) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

DPYD p.Phe100fs

c.299_302del · rs72549309 · VCV495550

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, 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 4 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, 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 0.0148% European (non-Finnish) · 174/1,179,014 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0114% 184/1,612,634 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0148%	6,776
Remaining individualsnot grpmax-eligible	0.00961%	10,408
Admixed American	0.005%	19,994
African / African-American	0.00133%	74,984

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.Phe100fs
Coding: c.299_302del
MANE Select: NM_000110
dbSNP: rs72549309
Type: Microsatellite
Location: chr1:97740411 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 100: the 4fe-4s ferredoxin-type 1 domain

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 p.Cys385_Glu386delinsTer Likely pathogenic ★★ same condition
DPYD p.Ile370fs Pathogenic/Likely pathogenic ★★ same condition
DPYD p.Leu192fs Likely pathogenic ★ same condition
DPYD c.2177_2179+1del Likely pathogenic same condition
DPYD p.Ala348fs Likely pathogenic same condition
DPYD c.1340-2A>C Likely pathogenic ★★ same condition
DPYD c.1905+1G>C Pathogenic/Likely pathogenic ★★ same condition
DPYD c.1977_1983del 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-phe100fs (accessed [today's date]).

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