Is SUN2 p.Arg339Cys (c.1015C>T) pathogenic?

SUN2 p.Arg339Cys (c.1015C>T) is classified Uncertain significance in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: ambiguous (0.3991); Very rare (popmax 0.0022%, sas); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Arg339Cys (c.1015C>T)?

SUN2 p.Arg339Cys (c.1015C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Arg339Cys (c.1015C>T) in the general population?

SUN2 p.Arg339Cys (c.1015C>T) is very rare (popmax 0.0022%, sas) (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.Arg339Cys (c.1015C>T)?

AlphaMissense predicts ambiguous (score 0.3991) — an in-silico prediction, not a clinical call.

SUN2 p.Arg339Cys

c.1015C>T · rs754925148 · VCV2084824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.3991	ambiguous
REVEL	0.112	moderately benign-leaning
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.042, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 12 kb · p 0.11 · regional, not allelic
Overall
CADD	26.0	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 0.0022% South Asian · 2/91,030 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,611,846 alleles · very rare exomes 5/1,459,734 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,515
European (non-Finnish)	0.000339%	294,700

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.Arg339Cys
Coding: c.1015C>T
MANE Select: NM_015374
dbSNP: rs754925148
Type: single nucleotide variant
Location: chr22:38742354 (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.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
SUN2 p.Arg104Lys 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-arg339cys (accessed [today's date]).

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