Is DPYD p.Arg592Gln (c.1775G>A) pathogenic?

DPYD p.Arg592Gln (c.1775G>A) is classified Uncertain significance in DPYD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-11-14). AlphaMissense: likely benign (0.1896); Ultra-rare (popmax 0.0164%, mid); Associated with dihydropyrimidine dehydrogenase deficiency.

What condition is associated with DPYD p.Arg592Gln (c.1775G>A)?

DPYD p.Arg592Gln (c.1775G>A) is associated with dihydropyrimidine dehydrogenase deficiency (ClinVar).

How common is DPYD p.Arg592Gln (c.1775G>A) in the general population?

DPYD p.Arg592Gln (c.1775G>A) is ultra-rare (popmax 0.0164%, 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.Arg592Gln (c.1775G>A)?

AlphaMissense predicts likely benign (score 0.1896) — an in-silico prediction, not a clinical call.

DPYD p.Arg592Gln

c.1775G>A · rs138616379 · VCV554703

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dihydropyrimidine dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1896	likely benign
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -16.50	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	29.0	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00483% 78/1,613,504 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.0107%	9,356
European (non-Finnish)	0.00559%	17,875
Admixed American	0.00167%	59,908
Remaining individualsnot grpmax-eligible	0.0016%	62,460
South Asian	0.0011%	91,072

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.Arg592Gln
Coding: c.1775G>A
MANE Select: NM_000110
dbSNP: rs138616379
Type: single nucleotide variant
Location: chr1:97450189 (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-arg592gln (accessed [today's date]).

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