Is DPYS p.Met70Thr (c.209T>C) pathogenic?

DPYS p.Met70Thr (c.209T>C) is classified Conflicting classifications of pathogenicity in DPYS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-29). AlphaMissense: likely pathogenic (0.8835); Ultra-rare (popmax 0.0664%, afr); Associated with dihydropyrimidinuria.

What condition is associated with DPYS p.Met70Thr (c.209T>C)?

DPYS p.Met70Thr (c.209T>C) is associated with dihydropyrimidinuria (ClinVar).

How common is DPYS p.Met70Thr (c.209T>C) in the general population?

DPYS p.Met70Thr (c.209T>C) is ultra-rare (popmax 0.0664%, afr) (gnomAD).

How is Dihydropyrimidinuria inherited?

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

What do computational predictors say about DPYS p.Met70Thr (c.209T>C)?

AlphaMissense predicts likely pathogenic (score 0.8835) — an in-silico prediction, not a clinical call.

DPYS p.Met70Thr

c.209T>C · rs370718225 · VCV2055236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8835 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0664%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dihydropyrimidinuria

Computational evidence

Protein change
AlphaMissense	0.8835	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -13.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	26.6	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 0.0664% African / African-American · 48/72,292 alleles

Filtering AF 0.0515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0461%

Overall 0.00352% 54/1,534,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0664%	1,506
Admixed American	0.00592%	16,900
Remaining individualsnot grpmax-eligible	0.00502%	19,938

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: DPYS
Protein: p.Met70Thr
Coding: c.209T>C
MANE Select: NM_001385
dbSNP: rs370718225
Type: single nucleotide variant
Location: chr8:104466712 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB

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

Disease context

dihydropyrimidinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dihydropyrimidinuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

DPYS p.Arg302Gln Likely pathogenic ★★ same condition
DPYS p.Arg302Ter Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg465Ter Pathogenic ★★ same condition
DPYS p.Arg475Ter Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg490Cys Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Arg490His Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Gln190Ter Pathogenic ★★ same condition
DPYS p.Gln334Arg 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/dpys-p-met70thr (accessed [today's date]).

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