Is SUN2 p.Pro219= (c.657G>A) pathogenic?

SUN2 p.Pro219= (c.657G>A) is classified Likely benign in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-11). Ultra-rare (popmax 0.0552%, nfe); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Pro219= (c.657G>A)?

SUN2 p.Pro219= (c.657G>A) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Pro219= (c.657G>A) in the general population?

SUN2 p.Pro219= (c.657G>A) is ultra-rare (popmax 0.0552%, 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.

SUN2 p.Pro219=

c.657G>A · rs143617240 · VCV1148837

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0552%, nfe)

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.072	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -2.6, phastCons 1
Overall
CADD	9.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0552% European (non-Finnish) · 651/1,180,040 alleles

Filtering AF 0.0516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.0429% 693/1,614,048 alleles · ultra-rare exomes 658/1,461,834 · genomes 35/152,214 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)grpmax	0.0552%	1,813
Remaining individualsnot grpmax-eligible	0.0352%	2,840
East Asian	0.0111%	8,980
African / African-American	0.00801%	12,483
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Admixed American	0.00333%	30,002
Finnishnot grpmax-eligible	0.00312%	32,014
South Asian	0.0022%	45,547

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro219=
Coding: c.657G>A
MANE Select: NM_015374
dbSNP: rs143617240
Type: single nucleotide variant
Location: chr22:38748741 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.48 · 9 PDB

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.Pro219Leu 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.Ala56Val 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-pro219 (accessed [today's date]).

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