Is SIK1 p.Pro696= (c.2088G>A) pathogenic?

SIK1 p.Pro696= (c.2088G>A) is classified Likely benign in SIK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-08). Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 30.

What condition is associated with SIK1 p.Pro696= (c.2088G>A)?

SIK1 p.Pro696= (c.2088G>A) is associated with developmental and epileptic encephalopathy, 30 (ClinVar).

How common is SIK1 p.Pro696= (c.2088G>A) in the general population?

SIK1 p.Pro696= (c.2088G>A) is absent from gnomAD v4.1 (gnomAD).

How is Infantile epileptic spasms syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SIK1 p.Pro696=

c.2088G>A · rs376915289 · VCV710885

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

developmental and epileptic encephalopathy, 30

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 -1.5	GERP -1.8, phastCons 0.04
Overall
CADD	3.502	PHRED · no single calibrated threshold — expert panels disagree

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: SIK1
Protein: p.Pro696=
Coding: c.2088G>A
MANE Select: NM_173354
dbSNP: rs376915289
Type: single nucleotide variant
Location: chr21:43417006 (GRCh38)
Structure: AlphaFold pLDDT 61.31
Residue 696: a UniProt-annotated variant site (in)

Full SIK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 30 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile epileptic spasms syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant

Similar variants

SIK1 p.Pro696Leu Benign/Likely benign ★★ same residue
SIK1 p.Pro696Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SIK1 c.273+4A>T Uncertain significance ★★ same condition
SIK1 p.Ala475Gly Uncertain significance ★★ ⚠ same condition
SIK1 p.Ala486Thr Uncertain significance ★★ ⚠ same condition
SIK1 p.Ala513Gly Uncertain significance ★★ ⚠ same condition
SIK1 p.Ala518Gly Uncertain significance ★★ ⚠ same condition
SIK1 p.Ala680Thr Uncertain significance ★★ ⚠ 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/sik1-p-pro696 (accessed [today's date]).

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