Is DPYD p.Ala538= (c.1614C>T) pathogenic?

DPYD p.Ala538= (c.1614C>T) is classified Uncertain significance in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0165%, mid); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Ala538= (c.1614C>T)?

DPYD p.Ala538= (c.1614C>T) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Ala538= (c.1614C>T) in the general population?

DPYD p.Ala538= (c.1614C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Dihydropyrimidine dehydrogenase deficiency inherited?

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

DPYD p.Ala538=

c.1614C>T · rs760853559 · VCV298288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

dihydropyrimidine dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -4.6, phastCons 0.005
Overall
CADD	7.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.00285% 46/1,612,714 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Admixed American	0.015%	6,647
Remaining individualsnot grpmax-eligible	0.00481%	20,799
European (non-Finnish)	0.00263%	38,040
East Asian	0.00223%	44,832
South Asian	0.0011%	91,060

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.Ala538=
Coding: c.1614C>T
MANE Select: NM_000110
dbSNP: rs760853559
Type: single nucleotide variant
Location: chr1:97515852 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.23

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-ala538 (accessed [today's date]).

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