Is DMPK p.Pro321Arg (c.962C>G) pathogenic?

DMPK p.Pro321Arg (c.962C>G) is classified Uncertain significance in DMPK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.0734); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with DMPK p.Pro321Arg (c.962C>G)?

DMPK p.Pro321Arg (c.962C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DMPK p.Pro321Arg (c.962C>G) in the general population?

DMPK p.Pro321Arg (c.962C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DMPK p.Pro321Arg (c.962C>G)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

DMPK p.Pro321Arg

c.962C>G · VCV3840507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -1.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.91 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP -1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 7,198 bp · p 0.0012 · regional, not allelic
Overall
CADD	16.66	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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,544 alleles · very rare exomes 9/1,461,212 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
European (non-Finnish)	0.000593%	168,574

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.Pro321Arg
Coding: c.962C>G
MANE Select: NM_004409
Type: single nucleotide variant
Location: chr19:45777511 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91 · 2 PDB
Residue 321: the protein kinase 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-pro321arg (accessed [today's date]).

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