Is SUN2 p.Arg339Leu (c.1016G>T) pathogenic?

SUN2 p.Arg339Leu (c.1016G>T) is classified Uncertain significance in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-02). AlphaMissense: ambiguous (0.4236); Very rare (popmax 0.0033%, sas); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Arg339Leu (c.1016G>T)?

SUN2 p.Arg339Leu (c.1016G>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Arg339Leu (c.1016G>T) in the general population?

SUN2 p.Arg339Leu (c.1016G>T) is very rare (popmax 0.0033%, 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.Arg339Leu (c.1016G>T)?

AlphaMissense predicts ambiguous (score 0.4236) — an in-silico prediction, not a clinical call.

SUN2 p.Arg339Leu

c.1016G>T · rs766230597 · VCV2323053

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Emery-Dreifuss muscular dystrophy

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.4236	ambiguous
REVEL	0.108	moderately benign-leaning
SaProt	LLR -8.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.58	GERP -0.004, phastCons 0.087
Regional constraint	o/e 0.94	unconstrained · MANE · 12 kb · p 0.11 · regional, not allelic
Overall
CADD	14.42	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 0.0033% South Asian · 3/91,022 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,611,996 alleles · very rare exomes 4/1,459,694 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,341
Remaining individualsnot grpmax-eligible	0.0016%	62,420

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.Arg339Leu
Coding: c.1016G>T
MANE Select: NM_015374
dbSNP: rs766230597
Type: single nucleotide variant
Location: chr22:38742353 (GRCh38)

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)

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-arg339leu (accessed [today's date]).

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