Is SYNGAP1 p.Pro66= (c.198C>T) pathogenic?

SYNGAP1 p.Pro66= (c.198C>T) is classified Benign in SYNGAP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 16.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with SYNGAP1 p.Pro66= (c.198C>T)?

SYNGAP1 p.Pro66= (c.198C>T) is associated with Inborn genetic diseases, intellectual disability, autosomal dominant 5 (ClinVar).

SYNGAP1 p.Pro66=

Q: How common is SYNGAP1 p.Pro66= (c.198C>T) in the general population?

SYNGAP1 p.Pro66= (c.198C>T) is common (popmax 16.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.198C>T · rs73402305 · VCV130527

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 16.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.41	GERP -2.1, phastCons 0.99
Overall
CADD	12.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.3% African / African-American · 12,217/74,928 alleles

Filtering AF 16.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 16%

Overall 0.866% 13,974/1,613,860 alleles · common exomes 7,282/1,461,728 · genomes 6,692/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	16.3%	6
Remaining individualsnot grpmax-eligible	1.01%	99
Admixed American	0.955%	105
Middle Eastern	0.925%	108
South Asian	0.0933%	1,071
European (non-Finnish)	0.0349%	2,864

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.Pro66=
Coding: c.198C>T
MANE Select: NM_006772
dbSNP: rs73402305
Type: single nucleotide variant
Location: chr6:33425806 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, autosomal dominant 5

Similar variants

SYNGAP1 p.Pro66Ser Benign ★ ⚠ same residue
SYNGAP1 p.Pro66Ala 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-pro66 (accessed [today's date]).

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