Is SYNGAP1 p.Ser129= (c.387G>A) pathogenic?

SYNGAP1 p.Ser129= (c.387G>A) is classified Likely pathogenic in SYNGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-16). Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Ser129= (c.387G>A)?

SYNGAP1 p.Ser129= (c.387G>A) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Ser129= (c.387G>A) in the general population?

SYNGAP1 p.Ser129= (c.387G>A) is absent from gnomAD v4.1 (gnomAD).

SYNGAP1 p.Ser129=

Q: How is SYNGAP1-related developmental and epileptic encephalopathy inherited?

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

c.387G>A · rs767126748 · VCV1066223

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.31	donor loss · deltas
Constraint at this position
Conservation	phyloP 9.2	GERP 0.46, phastCons 1
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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: SYNGAP1
Protein: p.Ser129=
Coding: c.387G>A
MANE Select: NM_006772
dbSNP: rs767126748
Type: single nucleotide variant
Location: chr6:33432252 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 129: the 'disordered' region

Full SYNGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For SYNGAP1-related developmental and epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy

Similar variants

SYNGAP1 p.Ser129fs Pathogenic ★ same residue
SYNGAP1 c.1532-1G>A Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 c.1676+1G>A Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 c.2294+1G>T Pathogenic ★★ same condition
SYNGAP1 c.3583-1G>A Likely pathogenic ★★ same condition
SYNGAP1 c.3583-6G>A Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 c.3583-9G>A Pathogenic ★★ same condition
SYNGAP1 c.509+1G>T 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/syngap1-p-ser129 (accessed [today's date]).

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