Is LMNA p.Arg527Pro (c.1580G>C) pathogenic?

LMNA p.Arg527Pro (c.1580G>C) is classified Pathogenic in LMNA (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9937); Absent from gnomAD v4.1; Associated with LMNA-related disorder.

What condition is associated with LMNA p.Arg527Pro (c.1580G>C)?

LMNA p.Arg527Pro (c.1580G>C) is associated with LMNA-related disorder, dilated cardiomyopathy, familial partial lipodystrophy, Dunnigan type (ClinVar).

How common is LMNA p.Arg527Pro (c.1580G>C) in the general population?

LMNA p.Arg527Pro (c.1580G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LMNA p.Arg527Pro (c.1580G>C)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

LMNA p.Arg527Pro

c.1580G>C · rs57520892 · VCV14481

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LMNA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic ✓ concordant with ClinVar · top 10% in LMNA
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -11.96	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 1.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,874 bp · p 0.0021 · regional, not allelic
Overall
CADD	32.0	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.Arg527Pro
Coding: c.1580G>C
MANE Select: NM_170707
dbSNP: rs57520892
Type: single nucleotide variant
Location: chr1:156137204 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 28 PDB
Residue 527: the 'tail' region; a UniProt-annotated variant site (in hgps); a UniProt-annotated variant site (in mada); a UniProt-annotated variant site (in edmd2 and fpld2; interacts with itself and with wild-type lmna and lmnb1; reduced binding to sun1; abnormal nuclear localization; forms nuclear foci in about 13% of cultured skin fibroblasts from heterozygous patients; no effect on protein level); a β-strand; the ltd domain

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

Disease context

Also linked: dilated cardiomyopathy familial partial lipodystrophy, Dunnigan type Charcot-Marie-Tooth disease type 2 Emery-Dreifuss muscular dystrophy 2, autosomal dominant

Similar variants

LMNA p.Arg527Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg527His Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg527Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg527fs 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.1157+2T>A 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-arg527pro (accessed [today's date]).

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