Is SUN2 p.Ala508Val (c.1523C>T) pathogenic?

SUN2 p.Ala508Val (c.1523C>T) is classified Uncertain significance in SUN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0841); Very rare (popmax 0.00878%, sas); Associated with Emery-Dreifuss muscular dystrophy.

What condition is associated with SUN2 p.Ala508Val (c.1523C>T)?

SUN2 p.Ala508Val (c.1523C>T) is associated with Emery-Dreifuss muscular dystrophy (ClinVar).

How common is SUN2 p.Ala508Val (c.1523C>T) in the general population?

SUN2 p.Ala508Val (c.1523C>T) is very rare (popmax 0.00878%, 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.Ala508Val (c.1523C>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

SUN2 p.Ala508Val

c.1523C>T · VCV3705753

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Emery-Dreifuss muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1.3, phastCons 0.51
Regional constraint	o/e 0.70	unconstrained · MANE · 2,037 bp · p 3.5e-07 · regional, not allelic
Overall
CADD	7.988	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00878% South Asian · 8/91,092 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00112% 18/1,613,500 alleles · very rare exomes 15/1,461,304 · genomes 3/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
East Asian	0.00223%	44,894
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,942
European (non-Finnish)	0.000593%	168,573

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.Ala508Val
Coding: c.1523C>T
MANE Select: NM_015374
Type: single nucleotide variant
Location: chr22:38739777 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.48 · 9 PDB
Residue 508: the 'sufficient for interaction with syne1 and syne2' region

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.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
SUN2 p.Arg121His 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-ala508val (accessed [today's date]).

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