Is LMNA p.Arg321Pro (c.962G>C) pathogenic?

LMNA p.Arg321Pro (c.962G>C) is classified Uncertain significance in LMNA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: likely pathogenic (0.9691); Very rare (popmax 8.48e-05%, nfe); Associated with dilated cardiomyopathy.

What condition is associated with LMNA p.Arg321Pro (c.962G>C)?

LMNA p.Arg321Pro (c.962G>C) is associated with dilated cardiomyopathy (ClinVar).

How common is LMNA p.Arg321Pro (c.962G>C) in the general population?

LMNA p.Arg321Pro (c.962G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about LMNA p.Arg321Pro (c.962G>C)?

AlphaMissense predicts likely pathogenic (score 0.9691) — an in-silico prediction, not a clinical call.

LMNA p.Arg321Pro

c.962G>C · rs1180922815 · VCV3070304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9691	likely pathogenic
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -13.77	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 12	GERP -1.1, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 63 bp · p 0.34 · regional, not allelic
Overall
CADD	31.0	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 8.48e-05% European (non-Finnish) · 1/1,179,936 alleles

Overall 6.84e-05% 1/1,461,516 alleles · very rare

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: LMNA
Protein: p.Arg321Pro
Coding: c.962G>C
MANE Select: NM_170707
dbSNP: rs1180922815
Type: single nucleotide variant
Location: chr1:156135926 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 28 PDB
Residue 321: the 'coil 2' region; the 'necessary and sufficient for the interaction with iffo1' region; an α-helix; the if rod domain

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

Disease context

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

Similar variants

LMNA p.Arg321Ter Pathogenic ★★ same residue
LMNA p.Arg321Gln Uncertain significance ★★ ⚠ same residue
LMNA c.1157+2T>A Pathogenic ★★ same condition
LMNA c.1609-1G>A Pathogenic/Likely pathogenic ★★ same condition
LMNA c.1609-3C>G Pathogenic/Likely pathogenic ★★ same condition
LMNA c.356+1G>C Pathogenic/Likely pathogenic ★★ same condition
LMNA c.513+1G>C Likely pathogenic ★★ same condition
LMNA p.Arg166Pro Pathogenic/Likely 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/lmna-p-arg321pro (accessed [today's date]).

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