Is DPYS p.Pro299Ser (c.895C>T) pathogenic?

DPYS p.Pro299Ser (c.895C>T) is classified Uncertain significance in DPYS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-05). AlphaMissense: likely pathogenic (0.9658); Ultra-rare (popmax 0.0137%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DPYS p.Pro299Ser (c.895C>T)?

DPYS p.Pro299Ser (c.895C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DPYS p.Pro299Ser (c.895C>T) in the general population?

DPYS p.Pro299Ser (c.895C>T) is ultra-rare (popmax 0.0137%, nfe) (gnomAD).

What do computational predictors say about DPYS p.Pro299Ser (c.895C>T)?

AlphaMissense predicts likely pathogenic (score 0.9658) — an in-silico prediction, not a clinical call.

DPYS p.Pro299Ser

c.895C>T · rs759626469 · VCV2213094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9658	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -12.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0137% European (non-Finnish) · 162/1,180,030 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0102% 165/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0137%	7,284
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Pro299Ser
Coding: c.895C>T
MANE Select: NM_001385
dbSNP: rs759626469
Type: single nucleotide variant
Location: chr8:104429600 (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

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

Similar variants

DPYS p.Ser379Arg Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Ala47Gly Uncertain significance ★★ ⚠ same condition
DPYS p.Ala491Val Uncertain significance ★★ ⚠ same condition
DPYS p.Asn347Ser Uncertain significance ★★ ⚠ same condition
DPYS p.Asp140Asn Uncertain significance ★★ ⚠ same condition
DPYS p.Asp309Tyr Uncertain significance ★★ ⚠ same condition
DPYS p.Glu115Lys Uncertain significance ★★ ⚠ same condition
DPYS p.Gly216Asp 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/dpys-p-pro299ser (accessed [today's date]).

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