Is ANK3 p.Arg1456fs (c.4365_4368del) pathogenic?

ANK3 p.Arg1456fs (c.43654368del) is classified Pathogenic/Likely pathogenic in ANK3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-18). Very rare (popmax 8.53e-05%, nfe); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Arg1456fs (c.4365_4368del)?

ANK3 p.Arg1456fs (c.4365_4368del) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Arg1456fs (c.4365_4368del) in the general population?

ANK3 p.Arg1456fs (c.4365_4368del) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

ANK3 p.Arg1456fs

Q: How is ANK3-related intellectual disability-sleep disturbance syndrome inherited?

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

c.4365_4368del · rs2084966849 · VCV872695

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 36 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 3.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,840 alleles

Overall 6.95e-05% 1/1,439,176 alleles · very rare

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: ANK3
Protein: p.Arg1456fs
Coding: c.4365_4368del
MANE Select: NM_020987
dbSNP: rs2084966849
Type: Deletion
Location: chr10:60080601 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)

Full ANK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability-hypotonia-spasticity-sleep disorder syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ANK3-related intellectual disability-sleep disturbance syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ANK3 p.Ala1197fs Pathogenic ★ same condition
ANK3 p.Glu3465fs Uncertain significance ★ same condition
ANK3 p.Pro3678fs Pathogenic same condition
ANK3 p.Thr3666fs Pathogenic same condition
ANK3 p.Ala1630Val Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala2023Thr Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala628Thr Uncertain significance ★★ same condition
ANK3 p.Arg1243His 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/ank3-p-arg1456fs (accessed [today's date]).

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