Is SYNGAP1 p.Ser52= (c.156G>A) pathogenic?

SYNGAP1 p.Ser52= (c.156G>A) is classified Likely benign in SYNGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-17). Very rare (popmax 0.00333%, amr); Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Ser52= (c.156G>A)?

SYNGAP1 p.Ser52= (c.156G>A) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Ser52= (c.156G>A) in the general population?

SYNGAP1 p.Ser52= (c.156G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

SYNGAP1 p.Ser52=

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.156G>A · rs1554304681 · VCV436921

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

intellectual disability, autosomal dominant 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -1.4, phastCons 1
Overall
CADD	14.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,614,170 alleles · very rare exomes 7/1,461,864 · genomes 1/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,010
African / African-American	0.00133%	75,028
South Asian	0.0011%	91,084
European (non-Finnish)	0.000339%	295,007

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.Ser52=
Coding: c.156G>A
MANE Select: NM_006772
dbSNP: rs1554304681
Type: single nucleotide variant
Location: chr6:33423565 (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.Ser52Ter Pathogenic ★ same residue
SYNGAP1 p.Ser52Leu 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-ser52 (accessed [today's date]).

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