Is SYNGAP1 p.Phe218= (c.654C>T) pathogenic?

SYNGAP1 p.Phe218= (c.654C>T) is classified Likely benign in SYNGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). Very rare (popmax 0.0011%, sas); Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Phe218= (c.654C>T)?

SYNGAP1 p.Phe218= (c.654C>T) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Phe218= (c.654C>T) in the general population?

SYNGAP1 p.Phe218= (c.654C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

SYNGAP1 p.Phe218=

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.654C>T · rs542048435 · VCV698902

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 2.2	GERP 1.1, phastCons 1
Overall
CADD	12.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,022 alleles

Overall 0.000186% 3/1,612,868 alleles · very rare exomes 2/1,460,742 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,402
South Asiangrpmax	0.0011%	91,022
European (non-Finnish)	8.47e-05%	1,180,013

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe218=
Coding: c.654C>T
MANE Select: NM_006772
dbSNP: rs542048435
Type: single nucleotide variant
Location: chr6:33435296 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 218: the ph domain; a UniProt-annotated variant site (in mrd5; uncertain significance)

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.Phe218fs Pathogenic ★★ 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-phe218 (accessed [today's date]).

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