Is SUN2 p.Ala56Pro (c.166G>C) pathogenic?

SUN2 p.Ala56Pro (c.166G>C) is classified Uncertain significance in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0904); Ultra-rare (popmax 0.0997%, nfe); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Ala56Pro (c.166G>C)?

SUN2 p.Ala56Pro (c.166G>C) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Ala56Pro (c.166G>C) in the general population?

SUN2 p.Ala56Pro (c.166G>C) is ultra-rare (popmax 0.0997%, nfe) (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 SUN2 p.Ala56Pro (c.166G>C)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

SUN2 p.Ala56Pro

c.166G>C · rs137966643 · VCV530819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0997%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.655	pathogenic-leaning
SaProt	LLR -6.13	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.1, phastCons 0.003
Regional constraint	o/e 0.94	unconstrained · MANE · 12 kb · p 0.11 · regional, not allelic
Overall
CADD	20.6	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 0.0997% European (non-Finnish) · 1,176/1,180,026 alleles

Filtering AF 0.0949% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.093%

Overall 0.0756% 1,220/1,613,954 alleles · ultra-rare exomes 1,162/1,461,762 · genomes 58/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0997%	1,003
Remaining individualsnot grpmax-eligible	0.032%	3,124
Admixed American	0.0183%	5,454
African / African-American	0.016%	6,243
Finnishnot grpmax-eligible	0.00156%	63,940

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: SUN2
Protein: p.Ala56Pro
Coding: c.166G>C
MANE Select: NM_015374
dbSNP: rs137966643
Type: single nucleotide variant
Location: chr22:38751330 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.48 · 9 PDB
Residue 56: the 'lmna-binding' region; the 'disordered' region

Full SUN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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

SUN2 p.Ala56Val Uncertain significance ★★ ⚠ same residue
SUN2 p.Ala56= Likely benign ★ same residue
SUN2 p.Ala158Thr Uncertain significance ★★ ⚠ same condition
SUN2 p.Ala251Val Uncertain significance ★★ ⚠ same condition
SUN2 p.Ala508Val Uncertain significance ★★ ⚠ same condition
SUN2 p.Arg100Gln Uncertain significance ★★ ⚠ same condition
SUN2 p.Arg102Gln Uncertain significance ★★ ⚠ same condition
SUN2 p.Arg102Trp Uncertain significance ★★ ⚠ 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/sun2-p-ala56pro (accessed [today's date]).

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