Is SYNGAP1 p.Pro89Ala (c.265C>G) pathogenic?

SYNGAP1 p.Pro89Ala (c.265C>G) is classified Conflicting classifications of pathogenicity in SYNGAP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.9197); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Pro89Ala (c.265C>G)?

SYNGAP1 p.Pro89Ala (c.265C>G) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Pro89Ala (c.265C>G) in the general population?

SYNGAP1 p.Pro89Ala (c.265C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNGAP1 p.Pro89Ala (c.265C>G)?

AlphaMissense predicts likely pathogenic (score 0.9197) — an in-silico prediction, not a clinical call.

SYNGAP1 p.Pro89Ala

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.265C>G · rs1776944236 · VCV1031674

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9197 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
AlphaMissense	0.9197	likely pathogenic
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.1, phastCons 1
Overall
CADD	24.4	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

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.Pro89Ala
Coding: c.265C>G
MANE Select: NM_006772
dbSNP: rs1776944236
Type: single nucleotide variant
Location: chr6:33425873 (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.Pro89Ser Uncertain significance ★ ⚠ same residue
SYNGAP1 p.Pro89Leu 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
SYNGAP1 c.3583-9G>A 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-pro89ala (accessed [today's date]).

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