Is SIK1 p.Phe26Val (c.76T>G) pathogenic?

SIK1 p.Phe26Val (c.76T>G) is classified Uncertain significance in SIK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely pathogenic (0.9669); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 30.

What condition is associated with SIK1 p.Phe26Val (c.76T>G)?

SIK1 p.Phe26Val (c.76T>G) is associated with developmental and epileptic encephalopathy, 30 (ClinVar).

How common is SIK1 p.Phe26Val (c.76T>G) in the general population?

SIK1 p.Phe26Val (c.76T>G) 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.

What do computational predictors say about SIK1 p.Phe26Val (c.76T>G)?

AlphaMissense predicts likely pathogenic (score 0.9669) — an in-silico prediction, not a clinical call.

SIK1 p.Phe26Val

c.76T>G · rs2081066253 · VCV852259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9669 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 30

Computational evidence

Protein change
AlphaMissense	0.9669	likely pathogenic
REVEL	0.185	benign-leaning
SaProt	LLR -13.09	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 6.8, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 9,433 bp · p 0.14 · regional, not allelic
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: SIK1
Protein: p.Phe26Val
Coding: c.76T>G
MANE Select: NM_173354
dbSNP: rs2081066253
Type: single nucleotide variant
Location: chr21:43426103 (GRCh38)
Structure: AlphaFold pLDDT 61.31

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 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
SIK1 p.Arg257Cys 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-phe26val (accessed [today's date]).

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