Is DPYS p.Leu337Pro (c.1010T>C) pathogenic?

DPYS p.Leu337Pro (c.1010T>C) is classified Uncertain significance in DPYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely pathogenic (0.7308); Rare (popmax 0.249%, sas).

How common is DPYS p.Leu337Pro (c.1010T>C) in the general population?

DPYS p.Leu337Pro (c.1010T>C) is rare (popmax 0.249%, sas) (gnomAD).

What do computational predictors say about DPYS p.Leu337Pro (c.1010T>C)?

AlphaMissense predicts likely pathogenic (score 0.7308) — an in-silico prediction, not a clinical call.

DPYS p.Leu337Pro

c.1010T>C · rs530911437 · VCV1001764

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7308 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.249%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7308	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -12.43	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 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	28.9	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 0.249% South Asian · 227/91,088 alleles

Filtering AF 0.223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.212%

Overall 0.0148% 239/1,614,174 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.249%	401
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)	8.47e-05%	1,179,967

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.Leu337Pro
Coding: c.1010T>C
MANE Select: NM_001385
dbSNP: rs530911437
Type: single nucleotide variant
Location: chr8:104428062 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB
Residue 337: an α-helix

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

Similar variants

DPYS c.424-1G>A Pathogenic/Likely pathogenic ★★ same type
DPYS p.Arg302Gln Likely pathogenic ★★ same type
DPYS p.Arg302Ter Pathogenic/Likely pathogenic ★★ same type
DPYS p.Arg465Ter Pathogenic ★★ same type
DPYS p.Arg475Ter Pathogenic/Likely pathogenic ★★ same type
DPYS p.Arg490Cys Pathogenic/Likely pathogenic ★★ same type
DPYS p.Arg490His Pathogenic/Likely pathogenic ★★ same type
DPYS p.Gln190Ter 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/dpys-p-leu337pro (accessed [today's date]).

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