Is DPYD p.Arg74Ter (c.220C>T) pathogenic?

DPYD p.Arg74Ter (c.220C>T) is classified Conflicting classifications of pathogenicity in DPYD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-10-03). Ultra-rare (popmax 0.0714%, eas); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Arg74Ter (c.220C>T)?

DPYD p.Arg74Ter (c.220C>T) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Arg74Ter (c.220C>T) in the general population?

DPYD p.Arg74Ter (c.220C>T) is ultra-rare (popmax 0.0714%, eas) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

DPYD p.Arg74Ter

c.220C>T · rs189768576 · VCV370757

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0714%, eas)

Conditions

dihydropyrimidine dehydrogenase deficiency

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 3 of 23
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.1, phastCons 1
Overall
CADD	41.0	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 0.0714% East Asian · 32/44,842 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0453%

Overall 0.00291% 47/1,613,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0714%	1,401
Admixed American	0.0133%	7,497
African / African-American	0.004%	24,987
South Asian	0.0022%	45,530
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	8.48e-05%	1,179,778

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.Arg74Ter
Coding: c.220C>T
MANE Select: NM_000110
dbSNP: rs189768576
Type: single nucleotide variant
Location: chr1:97828127 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 74: 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 c.1340-2A>C Likely pathogenic ★★ same condition
DPYD c.1905+1G>C Pathogenic/Likely pathogenic ★★ same condition
DPYD c.233+1G>T Likely pathogenic ★★ same condition
DPYD c.2622+1G>A Likely pathogenic ★★ same condition
DPYD c.2767-1G>A Likely pathogenic ★★ same condition
DPYD c.680+1G>T Likely pathogenic ★★ same condition
DPYD p.Arg21Ter Pathogenic/Likely pathogenic ★★ same condition
DPYD p.Arg561Ter Pathogenic/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-arg74ter (accessed [today's date]).

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