Is ANK3 p.Ser1569Ala (c.4705T>G) pathogenic?

ANK3 p.Ser1569Ala (c.4705T>G) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-04-06). AlphaMissense: likely benign (0.1453); Rare (popmax 0.512%, mid); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Ser1569Ala (c.4705T>G)?

ANK3 p.Ser1569Ala (c.4705T>G) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome, autism (ClinVar).

How common is ANK3 p.Ser1569Ala (c.4705T>G) in the general population?

ANK3 p.Ser1569Ala (c.4705T>G) is rare (popmax 0.512%, mid) (gnomAD).

What do computational predictors say about ANK3 p.Ser1569Ala (c.4705T>G)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

ANK3 p.Ser1569Ala

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.4705T>G · rs375050420 · VCV88649

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.512%, mid)

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.324	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 5.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,641 bp · p 6.9e-05 · regional, not allelic
Overall
CADD	23.6	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

Grpmax group 0.512% Middle Eastern · 31/6,060 alleles

Filtering AF 0.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.322%

Overall 0.00446% 72/1,614,188 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.512%	195
Admixed American	0.00833%	12,006
South Asian	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.0022%	45,384

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.Ser1569Ala
Coding: c.4705T>G
MANE Select: NM_020987
dbSNP: rs375050420
Type: single nucleotide variant
Location: chr10:60076176 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 1569: a UniProt-annotated variant site (found in a patient with autism; uncertain significance)

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

Also linked: autism

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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
ANK3 p.Arg1575Trp Uncertain significance ★★ same condition
ANK3 p.Arg2239Cys Uncertain significance ★★ ⚠ same condition
ANK3 p.Arg852His Uncertain significance ★★ ⚠ same condition
ANK3 p.Asn224Ser 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-ser1569ala (accessed [today's date]).

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