Is LMNA p.Arg166Pro (c.497G>C) pathogenic?

LMNA p.Arg166Pro (c.497G>C) is classified Pathogenic/Likely pathogenic in LMNA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.9688); Very rare (popmax 0.000171%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LMNA p.Arg166Pro (c.497G>C)?

LMNA p.Arg166Pro (c.497G>C) is associated with Cardiovascular phenotype, dilated cardiomyopathy, dilated cardiomyopathy 1A (ClinVar).

How common is LMNA p.Arg166Pro (c.497G>C) in the general population?

LMNA p.Arg166Pro (c.497G>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about LMNA p.Arg166Pro (c.497G>C)?

AlphaMissense predicts likely pathogenic (score 0.9688) — an in-silico prediction, not a clinical call.

LMNA p.Arg166Pro

c.497G>C · rs267607570 · VCV66901

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9688	likely pathogenic ✓ concordant with ClinVar
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -15.12	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 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 21 kb · p 3e-16 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.000171% European (non-Finnish) · 2/1,167,926 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,589,196 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.Arg166Pro
Coding: c.497G>C
MANE Select: NM_170707
dbSNP: rs267607570
Type: single nucleotide variant
Location: chr1:156130757 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 28 PDB
Residue 166: the 'coil 1b' region; a UniProt-annotated variant site (in cmd1a; dramatically aberrant localization with almost no nuclear rim staining and formation of intranuclear foci); an α-helix; the if rod domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy dilated cardiomyopathy 1A Charcot-Marie-Tooth disease type 2

Similar variants

LMNA p.Arg166Gly Likely pathogenic ★ same residue
LMNA p.Arg166= Conflicting classifications of pathogenicity ★ same residue
LMNA p.Arg166Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Arg166Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg166pro (accessed [today's date]).

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