Is SUN1 p.Ala593Val (c.1778C>T) pathogenic?

SUN1 p.Ala593Val (c.1778C>T) is classified Uncertain significance in SUN1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-26). Ultra-rare (popmax 0.0183%, amr); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN1 p.Ala593Val (c.1778C>T)?

SUN1 p.Ala593Val (c.1778C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN1 p.Ala593Val (c.1778C>T) in the general population?

SUN1 p.Ala593Val (c.1778C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Emery-Dreifuss muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SUN1 p.Ala593Val

c.1778C>T · rs765019636 · VCV2079929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.1	moderately benign-leaning
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.8	GERP 4.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 13 kb · p 0.0008 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,984 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00118% 19/1,610,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
Middle Eastern	0.0168%	5,936
East Asian	0.00446%	22,404
African / African-American	0.00134%	74,876
European (non-Finnish)	0.00034%	294,429

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: SUN1
Protein: p.Ala593Val
Coding: c.1778C>T
MANE Select: NM_001130965
dbSNP: rs765019636
Type: single nucleotide variant
Location: chr7:860381 (GRCh38)
Gene constraint: LOEUF 0.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 8 PDB
Residue 593: an α-helix; the 'sufficient for interaction with syne1 and syne2' region

Full SUN1 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

SUN1 p.Ala593Ser Uncertain significance ★ same residue
SUN1 p.Ala179Thr Uncertain significance ★★ same condition
SUN1 p.Ala203Thr Uncertain significance ★★ same condition
SUN1 p.Ala232Val Uncertain significance ★★ same condition
SUN1 p.Ala236Thr Uncertain significance ★★ same condition
SUN1 p.Ala255Thr Uncertain significance ★★ same condition
SUN1 p.Ala256Val Uncertain significance ★★ same condition
SUN1 p.Ala404Thr 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/sun1-p-ala593val (accessed [today's date]).

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