Is SYNGAP1 p.Pro1104Ser (c.3310C>T) pathogenic?

SYNGAP1 p.Pro1104Ser (c.3310C>T) is classified Benign in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.073); Very rare (popmax 8.8e-05%, nfe); Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Pro1104Ser (c.3310C>T)?

SYNGAP1 p.Pro1104Ser (c.3310C>T) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Pro1104Ser (c.3310C>T) in the general population?

SYNGAP1 p.Pro1104Ser (c.3310C>T) is very rare (popmax 8.8e-05%, nfe) (gnomAD).

What do computational predictors say about SYNGAP1 p.Pro1104Ser (c.3310C>T)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

SYNGAP1 p.Pro1104Ser

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.3310C>T · rs1761119731 · VCV2912797

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.8e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Overall
CADD	20.4	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 8.8e-05% European (non-Finnish) · 1/1,136,884 alleles

Overall 6.54e-05% 1/1,529,126 alleles · very rare exomes 0/1,377,188 · genomes 1/151,938 · joint denominator

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.Pro1104Ser
Coding: c.3310C>T
MANE Select: NM_006772
dbSNP: rs1761119731
Type: single nucleotide variant
Location: chr6:33443862 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 1104: a UniProt-annotated variant site (in mrd5; uncertain significance); a UniProt-annotated variant site (in mrd5); 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.Pro1104= Likely benign ★ 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-pro1104ser (accessed [today's date]).

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