Is SYNE2 p.Lys891Arg (c.2672A>G) pathogenic?

SYNE2 p.Lys891Arg (c.2672A>G) is classified Uncertain significance in SYNE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely benign (0.0851); Very rare (popmax 0.00168%, amr); Associated with Emery-Dreifuss muscular dystrophy 5, autosomal dominant.

What condition is associated with SYNE2 p.Lys891Arg (c.2672A>G)?

SYNE2 p.Lys891Arg (c.2672A>G) is associated with Emery-Dreifuss muscular dystrophy 5, autosomal dominant (ClinVar).

How common is SYNE2 p.Lys891Arg (c.2672A>G) in the general population?

SYNE2 p.Lys891Arg (c.2672A>G) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about SYNE2 p.Lys891Arg (c.2672A>G)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

SYNE2 p.Lys891Arg

c.2672A>G · rs2096689692 · VCV3000130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.39, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 116 kb · p 0.18 · regional, not allelic
Overall
CADD	11.76	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,414 alleles

Overall 6.21e-05% 1/1,610,210 alleles · very rare exomes 1/1,457,902 · genomes 0/152,308 · joint denominator

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: SYNE2
Protein: p.Lys891Arg
Coding: c.2672A>G
MANE Select: NM_182914
dbSNP: rs2096689692
Type: single nucleotide variant
Location: chr14:63993860 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI <0.01 (gnomAD)

Full SYNE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Emery-Dreifuss muscular dystrophy 5, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SYNE2 c.12108+3A>G Uncertain significance ★★ same condition
SYNE2 c.12609+1G>A Uncertain significance ★★ same condition
SYNE2 c.13159-3C>T Uncertain significance ★★ same condition
SYNE2 c.13159-7A>G Uncertain significance ★★ same condition
SYNE2 c.15484-3T>C Uncertain significance ★★ same condition
SYNE2 c.2313+1G>A Uncertain significance ★★ same condition
SYNE2 c.2647-2A>G Uncertain significance ★★ same condition
SYNE2 c.5960+6G>A 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/syne2-p-lys891arg (accessed [today's date]).

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