Is DPYD p.Met377Val (c.1129A>G) pathogenic?

DPYD p.Met377Val (c.1129A>G) is classified Uncertain significance in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2014-11-05). AlphaMissense: likely benign (0.0596); Ultra-rare (popmax 0.0347%, afr); Associated with Inborn genetic diseases.

What condition is associated with DPYD p.Met377Val (c.1129A>G)?

DPYD p.Met377Val (c.1129A>G) is associated with Inborn genetic diseases (ClinVar).

How common is DPYD p.Met377Val (c.1129A>G) in the general population?

DPYD p.Met377Val (c.1129A>G) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about DPYD p.Met377Val (c.1129A>G)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

DPYD p.Met377Val

c.1129A>G · rs144935781 · VCV985228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -4.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.095	GERP -3.9, phastCons 0.83
Regional constraint	o/e 1.04	unconstrained · MANE · 842 kb · p 0.18 · regional, not allelic
Overall
CADD	12.73	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0347% African / African-American · 26/75,012 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00211% 34/1,613,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,885
Admixed American	0.00501%	19,977
European (non-Finnish)	0.000424%	235,899

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.Met377Val
Coding: c.1129A>G
MANE Select: NM_000110
dbSNP: rs144935781
Type: single nucleotide variant
Location: chr1:97573970 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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DPYD p.Arg410Gln Uncertain significance ★★ ⚠ same condition
DPYD p.Arg692Gln Uncertain significance ★★ ⚠ same condition
DPYD p.Gln508= Uncertain significance ★★ same condition
DPYD p.Glu13Lys Uncertain significance ★★ ⚠ same condition
DPYD p.Glu950Lys Uncertain significance ★★ ⚠ 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-met377val (accessed [today's date]).

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