Is SYNGAP1 p.Arg596= (c.1788C>T) pathogenic?

SYNGAP1 p.Arg596= (c.1788C>T) is classified Likely benign in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). Very rare (popmax 0.00133%, afr); Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Arg596= (c.1788C>T)?

SYNGAP1 p.Arg596= (c.1788C>T) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Arg596= (c.1788C>T) in the general population?

SYNGAP1 p.Arg596= (c.1788C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

SYNGAP1 p.Arg596=

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.1788C>T · rs760758320 · VCV2803226

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 2.1, phastCons 1
Overall
CADD	16.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,076 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000681% 11/1,614,280 alleles · very rare exomes 11/1,461,892 · genomes 0/152,388 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,076
European (non-Finnish)	0.000847%	118,006

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: SYNGAP1
Protein: p.Arg596=
Coding: c.1788C>T
MANE Select: NM_006772
dbSNP: rs760758320
Type: single nucleotide variant
Location: chr6:33440840 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 596: the ras-gap domain; a UniProt-annotated variant site (in mrd5; uncertain significance); a UniProt-annotated variant site (in mrd5)

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.Arg596His Likely benign ★★ same residue
SYNGAP1 p.Arg596Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SYNGAP1 p.Arg596Leu Uncertain significance ★ ⚠ 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

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-arg596 (accessed [today's date]).

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