Is SNAP25 p.Ser154= (c.462C>T) pathogenic?

SNAP25 p.Ser154= (c.462C>T) is classified Likely benign in SNAP25 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00585%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SNAP25 p.Ser154= (c.462C>T)?

SNAP25 p.Ser154= (c.462C>T) is associated with Inborn genetic diseases, congenital myasthenic syndrome 18 (ClinVar).

How common is SNAP25 p.Ser154= (c.462C>T) in the general population?

SNAP25 p.Ser154= (c.462C>T) is very rare (popmax 0.00585%, nfe) (gnomAD).

SNAP25 p.Ser154=

c.462C>T · rs201639889 · VCV542729

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 2.4, phastCons 1
Overall
CADD	16.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00585% European (non-Finnish) · 69/1,179,968 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00576% 93/1,613,784 alleles · very rare exomes 86/1,461,764 · genomes 7/152,020 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)grpmax	0.00585%	17,101
Admixed American	0.005%	19,993
East Asian	0.00223%	44,866
South Asian	0.0011%	91,064

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser154=
Coding: c.462C>T
MANE Select: NM_130811
dbSNP: rs201639889
Type: single nucleotide variant
Location: chr20:10299322 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 14 PDB
Residue 154: a modified residue (phosphoserine); the t-snare coiled-coil homology 2 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 18

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-ser154 (accessed [today's date]).

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