Is SYNGAP1 p.Phe420Leu (c.1260T>G) pathogenic?

SYNGAP1 p.Phe420Leu (c.1260T>G) is classified Uncertain significance in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 5.

What condition is associated with SYNGAP1 p.Phe420Leu (c.1260T>G)?

SYNGAP1 p.Phe420Leu (c.1260T>G) is associated with intellectual disability, autosomal dominant 5 (ClinVar).

How common is SYNGAP1 p.Phe420Leu (c.1260T>G) in the general population?

SYNGAP1 p.Phe420Leu (c.1260T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNGAP1 p.Phe420Leu (c.1260T>G)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

SYNGAP1 p.Phe420Leu

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.1260T>G · rs2151170025 · VCV1397885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · 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	0.9983	likely pathogenic · top 3% in SYNGAP1
REVEL	0.146	moderately benign-leaning
SaProt	LLR -9.95	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 -1	GERP 0.14, phastCons 0.004
Overall
CADD	19.65	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.Phe420Leu
Coding: c.1260T>G
MANE Select: NM_006772
dbSNP: rs2151170025
Type: single nucleotide variant
Location: chr6:33438165 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.43
Residue 420: 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.Phe420= Likely benign ★ same residue
SYNGAP1 p.Phe420Ser Likely 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

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-phe420leu (accessed [today's date]).

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