Is DPYD p.Arg208Gln (c.623G>A) pathogenic?

DPYD p.Arg208Gln (c.623G>A) is classified Uncertain significance in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). AlphaMissense: likely pathogenic (0.7012); Very rare (popmax 0.000593%, nfe).

How common is DPYD p.Arg208Gln (c.623G>A) in the general population?

DPYD p.Arg208Gln (c.623G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about DPYD p.Arg208Gln (c.623G>A)?

AlphaMissense predicts likely pathogenic (score 0.7012) — an in-silico prediction, not a clinical call.

DPYD p.Arg208Gln

c.623G>A · rs376073289 · VCV2506135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7012	likely pathogenic
REVEL	0.648	pathogenic-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	28.5	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 0.000593% European (non-Finnish) · 7/1,179,686 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,494 alleles · very rare

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.Arg208Gln
Coding: c.623G>A
MANE Select: NM_000110
dbSNP: rs376073289
Type: single nucleotide variant
Location: chr1:97699408 (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

Similar variants

DPYD p.Arg208Leu Uncertain significance ★★ ⚠ same residue
DPYD p.Arg208Ter Likely pathogenic ★ same residue
DPYD c.1340-2A>C Likely pathogenic ★★ same type
DPYD c.1905+1G>C Pathogenic/Likely pathogenic ★★ same type
DPYD c.233+1G>T Likely pathogenic ★★ same type
DPYD c.2622+1G>A Likely pathogenic ★★ same type
DPYD c.2767-1G>A Likely pathogenic ★★ same type
DPYD c.680+1G>T Likely pathogenic ★★ same type

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-arg208gln (accessed [today's date]).

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