Is DPYD p.Pro86Leu (c.257C>T) pathogenic?

DPYD p.Pro86Leu (c.257C>T) is classified Pathogenic/Likely pathogenic in DPYD (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-11). AlphaMissense: likely pathogenic (0.8504); Rare (popmax 0.182%, mid); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Pro86Leu (c.257C>T)?

DPYD p.Pro86Leu (c.257C>T) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Pro86Leu (c.257C>T) in the general population?

DPYD p.Pro86Leu (c.257C>T) is rare (popmax 0.182%, mid) (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.Pro86Leu (c.257C>T)?

AlphaMissense predicts likely pathogenic (score 0.8504) — an in-silico prediction, not a clinical call.

DPYD p.Pro86Leu

c.257C>T · rs568132506 · VCV1028072

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.8504 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dihydropyrimidine dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.8504	likely pathogenic ✓ concordant with ClinVar
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -14.45	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	33.0	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

Grpmax group 0.182% Middle Eastern · 11/6,048 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0789%

Overall 0.00806% 130/1,612,888 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	550
Admixed American	0.0117%	8,569
European (non-Finnish)	0.00882%	11,340
Remaining individualsnot grpmax-eligible	0.008%	12,493
African / African-American	0.00267%	37,497
South Asian	0.0011%	91,066

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.Pro86Leu
Coding: c.257C>T
MANE Select: NM_000110
dbSNP: rs568132506
Type: single nucleotide variant
Location: chr1:97740456 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 86: 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.Pro86= Likely benign ★ same residue
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

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-pro86leu (accessed [today's date]).

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