Is SYNE1 p.Pro4486= (c.13458A>G) pathogenic?

SYNE1 p.Pro4486= (c.13458A>G) is classified Likely benign in SYNE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). Very rare (popmax 0.00237%, nfe); Associated with Emery-Dreifuss muscular dystrophy 4, autosomal dominant.

How common is SYNE1 p.Pro4486= (c.13458A>G) in the general population?

SYNE1 p.Pro4486= (c.13458A>G) is very rare (popmax 0.00237%, nfe) (gnomAD).

SYNE1 p.Pro4486=

Q: What condition is associated with SYNE1 p.Pro4486= (c.13458A>G)?

SYNE1 p.Pro4486= (c.13458A>G) is associated with Emery-Dreifuss muscular dystrophy 4, autosomal dominant, autosomal recessive ataxia, Beauce type (ClinVar).

c.13458A>G · rs998856849 · VCV1608873

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4
Overall
CADD	0.862	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,042 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,613,970 alleles · very rare exomes 26/1,461,752 · genomes 3/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: SYNE1
Protein: p.Pro4486=
Coding: c.13458A>G
MANE Select: NM_182961
dbSNP: rs998856849
Type: single nucleotide variant
Location: chr6:152331227 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)

Full SYNE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Emery-Dreifuss muscular dystrophy 4, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive ataxia, Beauce type

Similar variants

SYNE1 c.10145+1G>A Pathogenic/Likely pathogenic ★★ same condition
SYNE1 c.12079-2A>T Likely pathogenic ★★ same condition
SYNE1 c.15918-12A>G Pathogenic ★★ same condition
SYNE1 c.16390-2A>G Pathogenic/Likely pathogenic ★★ same condition
SYNE1 c.17682+1G>A Likely pathogenic ★★ same condition
SYNE1 c.19260+2T>C Likely pathogenic ★★ same condition
SYNE1 c.22044+1G>A Likely pathogenic ★★ same condition
SYNE1 c.23790+1G>A Likely pathogenic ★★ 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/syne1-p-pro4486 (accessed [today's date]).

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