Is LMNA p.Arg331Pro (c.992G>C) pathogenic?

LMNA p.Arg331Pro (c.992G>C) is classified Likely pathogenic in LMNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.9942); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with LMNA p.Arg331Pro (c.992G>C)?

LMNA p.Arg331Pro (c.992G>C) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is LMNA p.Arg331Pro (c.992G>C) in the general population?

LMNA p.Arg331Pro (c.992G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LMNA p.Arg331Pro (c.992G>C)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

LMNA p.Arg331Pro

c.992G>C · rs59301204 · VCV66963

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic ✓ concordant with ClinVar · top 10% in LMNA
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -15.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 63 bp · p 0.34 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LMNA
Protein: p.Arg331Pro
Coding: c.992G>C
MANE Select: NM_170707
dbSNP: rs59301204
Type: single nucleotide variant
Location: chr1:156135956 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 28 PDB
Residue 331: 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

Charcot-Marie-Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LMNA p.Arg331Gly Likely pathogenic ★ same residue
LMNA p.Arg331Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg331Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg331fs Pathogenic/Likely pathogenic ★★ same residue
LMNA p.Arg331Leu Likely pathogenic ★ same residue
LMNA c.1157+1G>A Pathogenic/Likely pathogenic ★★ same condition
LMNA c.1157+1G>T Pathogenic/Likely pathogenic ★★ same condition
LMNA c.1380+1G>A 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-arg331pro (accessed [today's date]).

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