Is ANK3 p.Ala2965= (c.8895T>C) pathogenic?

ANK3 p.Ala2965= (c.8895T>C) is classified Benign in ANK3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 27.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Ala2965= (c.8895T>C)?

ANK3 p.Ala2965= (c.8895T>C) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

ANK3 p.Ala2965=

Q: How common is ANK3 p.Ala2965= (c.8895T>C) in the general population?

ANK3 p.Ala2965= (c.8895T>C) is common (popmax 27.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.8895T>C · rs10740006 · VCV128380

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 27.4%, nfe) — too common for a highly-penetrant pathogenic allele

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -9.3
Overall
CADD	0.719	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.4% European (non-Finnish) · 322,872/1,179,940 alleles

Filtering AF 27.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.3%

Overall 24.3% 391,796/1,613,928 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	27.4%	4
Finnishnot grpmax-eligible	25.4%	4
Amishnot grpmax-eligible	25.1%	4
Remaining individualsnot grpmax-eligible	22.7%	4
Middle Eastern	22.5%	4
Ashkenazi Jewishnot grpmax-eligible	20.8%	5
Admixed American	18%	6
South Asian	15.9%	6
East Asian	4.79%	21
African / African-American	4.52%	22

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.Ala2965=
Coding: c.8895T>C
MANE Select: NM_020987
dbSNP: rs10740006
Type: single nucleotide variant
Location: chr10:60071986 (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.Ala2965Val Uncertain significance ★ ⚠ same residue
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

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-ala2965 (accessed [today's date]).

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