Is SNAP25 p.Arg59Pro (c.176G>C) pathogenic?

SNAP25 p.Arg59Pro (c.176G>C) is classified Uncertain significance in SNAP25 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-15). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy.

What condition is associated with SNAP25 p.Arg59Pro (c.176G>C)?

SNAP25 p.Arg59Pro (c.176G>C) is associated with developmental and epileptic encephalopathy (ClinVar).

How common is SNAP25 p.Arg59Pro (c.176G>C) in the general population?

SNAP25 p.Arg59Pro (c.176G>C) is absent from gnomAD v4.1 (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

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

What do computational predictors say about SNAP25 p.Arg59Pro (c.176G>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

SNAP25 p.Arg59Pro

c.176G>C · rs2064035728 · VCV1285531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 3% in SNAP25
REVEL	0.675	pathogenic-leaning
SaProt	LLR -17.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 21 kb · p 1.4e-16 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: SNAP25
Protein: p.Arg59Pro
Coding: c.176G>C
MANE Select: NM_130811
dbSNP: rs2064035728
Type: single nucleotide variant
Location: chr20:10293173 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 14 PDB
Residue 59: the t-snare coiled-coil homology 1 domain; the 'interaction with cenpf' region; an α-helix

Full SNAP25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

SNAP25 p.Arg59His Uncertain significance ★ same residue
SNAP25 p.Ala199Gly Pathogenic/Likely pathogenic ★★ same condition
SNAP25 p.Arg198Pro Likely pathogenic ★★ same condition
SNAP25 p.Gln197Ter Likely pathogenic ★★ same condition
SNAP25 p.Gly43Arg Pathogenic/Likely pathogenic ★★ same condition
SNAP25 p.Ile67Asn Pathogenic/Likely pathogenic ★★ same condition
SNAP25 p.Lys40Glu Likely pathogenic ★★ ⚠ same condition
SNAP25 p.Met71Thr Pathogenic/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/snap25-p-arg59pro (accessed [today's date]).

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