Is SYNE2 p.Pro4438Ser (c.13312C>T) pathogenic?

SYNE2 p.Pro4438Ser (c.13312C>T) is classified Uncertain significance in SYNE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-10). AlphaMissense: likely benign (0.0845); Absent from gnomAD v4.1; Associated with Emery-Dreifuss muscular dystrophy 5, autosomal dominant.

What condition is associated with SYNE2 p.Pro4438Ser (c.13312C>T)?

SYNE2 p.Pro4438Ser (c.13312C>T) is associated with Emery-Dreifuss muscular dystrophy 5, autosomal dominant (ClinVar).

How common is SYNE2 p.Pro4438Ser (c.13312C>T) in the general population?

SYNE2 p.Pro4438Ser (c.13312C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNE2 p.Pro4438Ser (c.13312C>T)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

SYNE2 p.Pro4438Ser

c.13312C>T · rs2549133143 · VCV1719155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.088	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 0.33	GERP -1.9
Regional constraint	o/e 1.02	unconstrained · MANE · 194 kb · p 0.085 · regional, not allelic
Overall
CADD	11.18	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SYNE2
Protein: p.Pro4438Ser
Coding: c.13312C>T
MANE Select: NM_182914
dbSNP: rs2549133143
Type: single nucleotide variant
Location: chr14:64122317 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI <0.01 (gnomAD)
Residue 4438: the 'disordered' region

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-pro4438ser (accessed [today's date]).

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