Is SYNGAP1 p.Ser28Pro (c.82T>C) pathogenic?

SYNGAP1 p.Ser28Pro (c.82T>C) is classified Uncertain significance in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-02). AlphaMissense: likely benign (0.0506); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Ser28Pro (c.82T>C)?

SYNGAP1 p.Ser28Pro (c.82T>C) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Ser28Pro (c.82T>C) in the general population?

SYNGAP1 p.Ser28Pro (c.82T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNGAP1 p.Ser28Pro (c.82T>C)?

AlphaMissense predicts likely benign (score 0.0506) — an in-silico prediction, not a clinical call.

SYNGAP1 p.Ser28Pro

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.82T>C · rs1776860607 · VCV1500161

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0506 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
AlphaMissense	0.0506	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.97	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 5.5	GERP 0.22, phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

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.Ser28Pro
Coding: c.82T>C
MANE Select: NM_006772
dbSNP: rs1776860607
Type: single nucleotide variant
Location: chr6:33423491 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43

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.Ser28= Benign/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-ser28pro (accessed [today's date]).

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