Is SUN2 p.Pro219Leu (c.656C>T) pathogenic?

SUN2 p.Pro219Leu (c.656C>T) is classified Benign in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.048); Low-frequency (popmax 3.47%, afr); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Pro219Leu (c.656C>T)?

SUN2 p.Pro219Leu (c.656C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Pro219Leu (c.656C>T) in the general population?

SUN2 p.Pro219Leu (c.656C>T) is low-frequency (popmax 3.47%, afr) (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.Pro219Leu (c.656C>T)?

AlphaMissense predicts likely benign (score 0.048) — an in-silico prediction, not a clinical call.

SUN2 p.Pro219Leu

c.656C>T · rs1883206 · VCV461691

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.048 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.47%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.048	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -3.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 12 kb · p 0.11 · regional, not allelic
Overall
CADD	14.86	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 3.47% African / African-American · 2,607/75,052 alleles

Filtering AF 3.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.32%

Overall 0.177% 2,853/1,614,222 alleles · low-frequency exomes 1,407/1,461,878 · genomes 1,446/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.47%	29
Remaining individualsnot grpmax-eligible	0.21%	477
Admixed American	0.123%	811
Middle Eastern	0.115%	866
South Asian	0.00439%	22,773
European (non-Finnish)	0.00254%	39,335

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.Pro219Leu
Coding: c.656C>T
MANE Select: NM_015374
dbSNP: rs1883206
Type: single nucleotide variant
Location: chr22:38748742 (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.Pro219= 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.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-pro219leu (accessed [today's date]).

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