Is LMNA p.Ser22Pro (c.64T>C) pathogenic?

LMNA p.Ser22Pro (c.64T>C) is classified Uncertain significance in LMNA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely pathogenic (0.9743); Absent from gnomAD v4.1; Associated with Emery-Dreifuss muscular dystrophy 3, autosomal recessive.

What condition is associated with LMNA p.Ser22Pro (c.64T>C)?

LMNA p.Ser22Pro (c.64T>C) is associated with Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy 1A, familial partial lipodystrophy, Dunnigan type (ClinVar).

How common is LMNA p.Ser22Pro (c.64T>C) in the general population?

LMNA p.Ser22Pro (c.64T>C) is absent from gnomAD v4.1 (gnomAD).

How is Emery-Dreifuss muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LMNA p.Ser22Pro (c.64T>C)?

AlphaMissense predicts likely pathogenic (score 0.9743) — an in-silico prediction, not a clinical call.

LMNA p.Ser22Pro

c.64T>C · VCV3595780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9743 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,595,888)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9743	likely pathogenic
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -11.85	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 3.4	GERP 0.21, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 21 kb · p 3e-16 · regional, not allelic
Overall
CADD	26.4	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

No allele count reported in gnomAD v4.1 (AN 1,595,888). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: LMNA
Protein: p.Ser22Pro
Coding: c.64T>C
MANE Select: NM_170707
Type: single nucleotide variant
Location: chr1:156114982 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 28 PDB
Residue 22: a β-strand; a modified residue (phosphoserine; by cdk1); the 'interaction with mlip' region; the 'head' region; the 'disordered' region

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

Disease context

Emery-Dreifuss muscular dystrophy 3, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1A familial partial lipodystrophy, Dunnigan type Hutchinson-Gilford progeria syndrome dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome mandibuloacral dysplasia with type A lipodystrophy Charcot-Marie-Tooth disease type 2B1 heart-hand syndrome, Slovenian type congenital muscular dystrophy due to LMNA mutation Emery-Dreifuss muscular dystrophy 2, autosomal dominant restrictive dermopathy 2

For Emery-Dreifuss muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

LMNA p.Ser22Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
LMNA p.Ser22= Likely benign ★★ same residue
LMNA c.1380+1G>A Pathogenic ★★ same condition
LMNA c.1608+1G>A Pathogenic ★★ same condition
LMNA c.1609-3C>G Pathogenic/Likely pathogenic ★★ same condition
LMNA c.640-10A>G Pathogenic/Likely pathogenic ★★ same condition
LMNA c.811-2A>G Pathogenic/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-ser22pro (accessed [today's date]).

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