Is DPYD p.Pro92Ala (c.274C>G) pathogenic?

DPYD p.Pro92Ala (c.274C>G) is classified Uncertain significance in DPYD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.6395); Ultra-rare (popmax 0.0152%, nfe); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Pro92Ala (c.274C>G)?

DPYD p.Pro92Ala (c.274C>G) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Pro92Ala (c.274C>G) in the general population?

DPYD p.Pro92Ala (c.274C>G) is ultra-rare (popmax 0.0152%, nfe) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

What do computational predictors say about DPYD p.Pro92Ala (c.274C>G)?

AlphaMissense predicts likely pathogenic (score 0.6395) — an in-silico prediction, not a clinical call.

DPYD p.Pro92Ala

c.274C>G · rs143986398 · VCV804763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6395 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dihydropyrimidine dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.6395	likely pathogenic
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -12.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0152% European (non-Finnish) · 179/1,179,504 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0126%

Overall 0.0121% 195/1,612,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0208%	4,804
European (non-Finnish)grpmax	0.0152%	6,589
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
African / African-American	0.00267%	37,425

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro92Ala
Coding: c.274C>G
MANE Select: NM_000110
dbSNP: rs143986398
Type: single nucleotide variant
Location: chr1:97740439 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 92: 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-pro92ala (accessed [today's date]).

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