Is SNAP25 p.Asp99Val (c.296A>T) pathogenic?

SNAP25 p.Asp99Val (c.296A>T) is classified Conflicting classifications of pathogenicity in SNAP25 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-30). AlphaMissense: ambiguous (0.4721); Very rare (popmax 0.00167%, amr); Associated with congenital myasthenic syndrome 18.

What condition is associated with SNAP25 p.Asp99Val (c.296A>T)?

SNAP25 p.Asp99Val (c.296A>T) is associated with congenital myasthenic syndrome 18 (ClinVar).

How common is SNAP25 p.Asp99Val (c.296A>T) in the general population?

SNAP25 p.Asp99Val (c.296A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SNAP25 p.Asp99Val (c.296A>T)?

AlphaMissense predicts ambiguous (score 0.4721) — an in-silico prediction, not a clinical call.

SNAP25 p.Asp99Val

c.296A>T · rs745741842 · VCV1394489

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

congenital myasthenic syndrome 18

Computational evidence

Protein change
AlphaMissense	0.4721	ambiguous
REVEL	0.207	benign-leaning
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 21 kb · p 1.4e-16 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,614,066 alleles · very rare exomes 17/1,461,834 · genomes 3/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.00153%	65,557
African / African-American	0.00133%	74,932

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: SNAP25
Protein: p.Asp99Val
Coding: c.296A>T
MANE Select: NM_130811
dbSNP: rs745741842
Type: single nucleotide variant
Location: chr20:10296939 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 14 PDB

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

Disease context

congenital myasthenic syndrome 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SNAP25 p.Ala199Glu 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
SNAP25 p.Ala2Thr 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/snap25-p-asp99val (accessed [today's date]).

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