Is DPYD p.Asp974Val (c.2921A>T) pathogenic?

DPYD p.Asp974Val (c.2921A>T) is classified Pathogenic in DPYD (ClinVar, No assertion criteria, 1 submitter; last evaluated 1997-01-01). AlphaMissense: likely benign (0.2727); Absent from gnomAD v4.1; Associated with 5-fluorouracil toxicity.

What condition is associated with DPYD p.Asp974Val (c.2921A>T)?

DPYD p.Asp974Val (c.2921A>T) is associated with 5-fluorouracil toxicity (ClinVar).

How common is DPYD p.Asp974Val (c.2921A>T) in the general population?

DPYD p.Asp974Val (c.2921A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DPYD p.Asp974Val (c.2921A>T)?

AlphaMissense predicts likely benign (score 0.2727) — an in-silico prediction, not a clinical call.

DPYD p.Asp974Val

c.2921A>T · rs72547602 · VCV433

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2727 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

5-fluorouracil toxicity

Computational evidence

Protein change
AlphaMissense	0.2727	likely benign ⚠ discordant with ClinVar
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DPYD
Protein: p.Asp974Val
Coding: c.2921A>T
MANE Select: NM_000110
dbSNP: rs72547602
Type: single nucleotide variant
Location: chr1:97079133 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 974: the 4fe-4s ferredoxin-type 2 domain

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

Disease context

5-fluorouracil toxicity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPYD c.1340-2A>C Likely pathogenic ★★ same type
DPYD c.1905+1G>C Pathogenic/Likely pathogenic ★★ same type
DPYD c.233+1G>T Likely pathogenic ★★ same type
DPYD c.2622+1G>A Likely pathogenic ★★ same type
DPYD c.2767-1G>A Likely pathogenic ★★ same type
DPYD c.680+1G>T Likely pathogenic ★★ same type
DPYD p.Arg21Ter Pathogenic/Likely pathogenic ★★ same type
DPYD p.Arg561Ter Pathogenic/Likely pathogenic ★★ same type

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-asp974val (accessed [today's date]).

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