Is ANK3 p.Ala628Thr (c.1882G>A) pathogenic?

ANK3 p.Ala628Thr (c.1882G>A) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-17). AlphaMissense: likely pathogenic (0.8158); Rare (popmax 0.182%, mid); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Ala628Thr (c.1882G>A)?

ANK3 p.Ala628Thr (c.1882G>A) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Ala628Thr (c.1882G>A) in the general population?

ANK3 p.Ala628Thr (c.1882G>A) is rare (popmax 0.182%, mid) (gnomAD).

What do computational predictors say about ANK3 p.Ala628Thr (c.1882G>A)?

AlphaMissense predicts likely pathogenic (score 0.8158) — an in-silico prediction, not a clinical call.

ANK3 p.Ala628Thr

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.1882G>A · rs540939855 · VCV389255

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8158 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.8158	likely pathogenic
REVEL	0.449	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 12 kb · p 1 · regional, not allelic
Overall
CADD	29.0	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 0.182% Middle Eastern · 11/6,054 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0788%

Overall 0.00198% 32/1,613,414 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	550
Remaining individualsnot grpmax-eligible	0.0096%	10,411
Admixed American	0.00667%	15,001
South Asian	0.00549%	18,207
African / African-American	0.00133%	74,998
European (non-Finnish)	0.000424%	235,896

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.Ala628Thr
Coding: c.1882G>A
MANE Select: NM_020987
dbSNP: rs540939855
Type: single nucleotide variant
Location: chr10:60196150 (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.Ala628Ser Uncertain significance ★ same residue
ANK3 p.Ala1630Val Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala2023Thr 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-ala628thr (accessed [today's date]).

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