Is SYNGAP1 p.Phe420Ser (c.1259T>C) pathogenic?

SYNGAP1 p.Phe420Ser (c.1259T>C) is classified Likely pathogenic in SYNGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-10). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with SYNGAP1 p.Phe420Ser (c.1259T>C)?

SYNGAP1 p.Phe420Ser (c.1259T>C) is associated with intellectual disability (ClinVar).

How common is SYNGAP1 p.Phe420Ser (c.1259T>C) in the general population?

SYNGAP1 p.Phe420Ser (c.1259T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYNGAP1 p.Phe420Ser (c.1259T>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

SYNGAP1 p.Phe420Ser

c.1259T>C · rs1760905358 · VCV981441

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 1% in SYNGAP1
REVEL	0.544	indeterminate
SaProt	LLR -14.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.2, phastCons 1
Overall
CADD	29.8	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.Phe420Ser
Coding: c.1259T>C
MANE Select: NM_006772
dbSNP: rs1760905358
Type: single nucleotide variant
Location: chr6:33438164 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SYNGAP1 p.Phe420Leu Uncertain significance ★ ⚠ same residue
SYNGAP1 p.Phe420= Likely benign ★ same residue
SYNGAP1 c.3583-6G>A Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 p.Arg135Ter Pathogenic ★★ same condition
SYNGAP1 p.Arg573Trp Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 p.Gln928Ter Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 p.Trp308Cys Pathogenic/Likely pathogenic ★★ same condition
SYNGAP1 p.Arg41Cys Conflicting classifications of pathogenicity ★ ⚠ 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-phe420ser (accessed [today's date]).

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