Is SIK1 p.Pro356= (c.1068C>T) pathogenic?

SIK1 p.Pro356= (c.1068C>T) is classified Likely benign in SIK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-05). Ultra-rare (popmax 0.0245%, sas); Associated with developmental and epileptic encephalopathy, 30.

What condition is associated with SIK1 p.Pro356= (c.1068C>T)?

SIK1 p.Pro356= (c.1068C>T) is associated with developmental and epileptic encephalopathy, 30 (ClinVar).

How common is SIK1 p.Pro356= (c.1068C>T) in the general population?

SIK1 p.Pro356= (c.1068C>T) is ultra-rare (popmax 0.0245%, sas) (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.Pro356=

c.1068C>T · rs776984333 · VCV735194

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, sas)

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 -10	GERP -3.6
Overall
CADD	0.689	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% South Asian · 1/4,082 alleles

Filtering AF 0.000934% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000349%

Overall 0.0104% 5/48,142 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0727%	1,375
South Asiangrpmax	0.0245%	4,082
European (non-Finnish)	0.00564%	17,744

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: SIK1
Protein: p.Pro356=
Coding: c.1068C>T
MANE Select: NM_173354
dbSNP: rs776984333
Type: single nucleotide variant
Location: chr21:43419910 (GRCh38)
Structure: AlphaFold pLDDT 61.31
Residue 356: the 'disordered' region

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.Pro356Ser 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
SIK1 p.Arg233Lys 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-pro356 (accessed [today's date]).

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