Is SUN2 p.Arg693Leu (c.2078G>T) pathogenic?

SUN2 p.Arg693Leu (c.2078G>T) is classified Uncertain significance in SUN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-03). AlphaMissense: likely pathogenic (0.6806); Ultra-rare (popmax 0.0103%, nfe); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Arg693Leu (c.2078G>T)?

SUN2 p.Arg693Leu (c.2078G>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Arg693Leu (c.2078G>T) in the general population?

SUN2 p.Arg693Leu (c.2078G>T) is ultra-rare (popmax 0.0103%, 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.Arg693Leu (c.2078G>T)?

AlphaMissense predicts likely pathogenic (score 0.6806) — an in-silico prediction, not a clinical call.

SUN2 p.Arg693Leu

c.2078G>T · rs137996727 · VCV2728453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL 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	0.6806	likely pathogenic
REVEL	0.378	indeterminate
SaProt	LLR -11.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,960 bp · p 0.7 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 121/1,179,888 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00768% 124/1,613,922 alleles · ultra-rare exomes 121/1,461,642 · genomes 3/152,280 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,751
African / African-American	0.00267%	37,515
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Arg693Leu
Coding: c.2078G>T
MANE Select: NM_015374
dbSNP: rs137996727
Type: single nucleotide variant
Location: chr22:38736343 (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-arg693leu (accessed [today's date]).

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