Is SYNGAP1 p.Pro528fs (c.1583delinsTG) pathogenic?

SYNGAP1 p.Pro528fs (c.1583delinsTG) is classified Likely pathogenic in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). No gnomAD frequency available for this variant; Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Pro528fs (c.1583delinsTG)?

SYNGAP1 p.Pro528fs (c.1583delinsTG) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Pro528fs (c.1583delinsTG) in the general population?

SYNGAP1 p.Pro528fs (c.1583delinsTG) is no gnomAD frequency available for this variant (gnomAD).

SYNGAP1 p.Pro528fs

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.1583delinsTG · rs2151172438 · VCV1527926

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SYNGAP1
Protein: p.Pro528fs
Coding: c.1583delinsTG
MANE Select: NM_006772
dbSNP: rs2151172438
Type: Indel
Location: chr6:33438826 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 528: 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.Pro528Leu Uncertain significance ★ ⚠ same residue
SYNGAP1 p.Glu360fs Pathogenic ★ same condition
SYNGAP1 p.Leu689fs Pathogenic ★ same condition
SYNGAP1 p.Thr294_Ser296delinsIleThrAla Likely pathogenic ★ same condition
SYNGAP1 p.Tyr518_Glu519delinsTer Pathogenic ★ same condition
SYNGAP1 p.Arg1070Thr Uncertain significance ★ same condition
SYNGAP1 p.Asn1334Asp Uncertain significance ★ same condition
SYNGAP1 c.189+15_189+16delinsGC Likely benign ★ 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-pro528fs (accessed [today's date]).

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