Is DPYD p.Cys91Phe (c.272G>T) pathogenic?

DPYD p.Cys91Phe (c.272G>T) is classified Uncertain significance in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-30). AlphaMissense: likely pathogenic (0.9873); Very rare (popmax 0.0028%, nfe); Associated with DPYD-related disorder.

What condition is associated with DPYD p.Cys91Phe (c.272G>T)?

DPYD p.Cys91Phe (c.272G>T) is associated with DPYD-related disorder (ClinVar).

How common is DPYD p.Cys91Phe (c.272G>T) in the general population?

DPYD p.Cys91Phe (c.272G>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about DPYD p.Cys91Phe (c.272G>T)?

AlphaMissense predicts likely pathogenic (score 0.9873) — an in-silico prediction, not a clinical call.

DPYD p.Cys91Phe

c.272G>T · rs928681171 · VCV2635856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DPYD-related disorder

Computational evidence

Protein change
AlphaMissense	0.9873	likely pathogenic · top 4% in DPYD
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -12.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	31.0	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 0.0028% European (non-Finnish) · 33/1,179,506 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00211% 34/1,613,008 alleles · very rare exomes 31/1,460,966 · genomes 3/152,042 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,743
African / African-American	0.00134%	74,866

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.Cys91Phe
Coding: c.272G>T
MANE Select: NM_000110
dbSNP: rs928681171
Type: single nucleotide variant
Location: chr1:97740441 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23
Residue 91: the 4fe-4s ferredoxin-type 1 domain; a binding site

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

Disease context

DPYD-related disorder

Similar variants

DPYD c.1340-2A>C Likely pathogenic ★★ same condition
DPYD p.Gln470Ter Likely pathogenic ★★ same condition
DPYD p.Glu221Ter Pathogenic/Likely pathogenic ★★ same condition
DPYD p.Ala729Val Uncertain significance ★★ ⚠ same condition
DPYD p.Gly258Ser Uncertain significance ★★ ⚠ same condition
DPYD p.Ile256Met Uncertain significance ★★ ⚠ same condition
DPYD p.Glu845Ter Likely pathogenic ★ same condition
DPYD p.Ala551Thr Conflicting classifications of pathogenicity ★ ⚠ 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-cys91phe (accessed [today's date]).

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