Is DMPK p.Pro399Leu (c.1196C>T) pathogenic?

DMPK p.Pro399Leu (c.1196C>T) is classified Uncertain significance in DMPK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely pathogenic (0.8068); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DMPK p.Pro399Leu (c.1196C>T)?

DMPK p.Pro399Leu (c.1196C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DMPK p.Pro399Leu (c.1196C>T) in the general population?

DMPK p.Pro399Leu (c.1196C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DMPK p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely pathogenic (score 0.8068) — an in-silico prediction, not a clinical call.

DMPK p.Pro399Leu

c.1196C>T · VCV3502663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8068	likely pathogenic
REVEL	0.661	pathogenic-leaning
SaProt	LLR -9.83	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 7,198 bp · p 0.0012 · regional, not allelic
Overall
CADD	29.9	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 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,613,890 alleles · very rare exomes 0/1,461,772 · genomes 1/152,118 · joint denominator

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: DMPK
Protein: p.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_004409
Type: single nucleotide variant
Location: chr19:45774985 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91 · 2 PDB
Residue 399: the agc-kinase c-terminal domain; an α-helix

Full DMPK 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

DMPK p.Pro257= Likely benign ★★ same condition
DMPK c.161-106C>A Uncertain significance ★ same condition
DMPK c.161-115A>G Uncertain significance ★ same condition
DMPK c.161-123A>C Uncertain significance ★ same condition
DMPK c.161-146G>A Uncertain significance ★ same condition
DMPK c.161-27G>T Uncertain significance ★ same condition
DMPK c.161-48G>C Uncertain significance ★ same condition
DMPK c.161-6C>T 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/dmpk-p-pro399leu (accessed [today's date]).

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