Is ANK3 p.Lys3123Arg (c.9368A>G) pathogenic?

ANK3 p.Lys3123Arg (c.9368A>G) is classified Benign in ANK3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0966); Common (popmax 27.3%, 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.Lys3123Arg (c.9368A>G)?

ANK3 p.Lys3123Arg (c.9368A>G) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

What do computational predictors say about ANK3 p.Lys3123Arg (c.9368A>G)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

ANK3 p.Lys3123Arg

Q: How common is ANK3 p.Lys3123Arg (c.9368A>G) in the general population?

ANK3 p.Lys3123Arg (c.9368A>G) is common (popmax 27.3%, 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.9368A>G · rs10821668 · VCV128385

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.094	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 5.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,360 bp · p 0.0017 · regional, not allelic
Overall
CADD	22.7	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 27.3% European (non-Finnish) · 322,515/1,179,904 alleles

Filtering AF 27.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.2%

Overall 24.2% 391,288/1,613,926 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	27.3%	4
Finnishnot grpmax-eligible	25.4%	4
Amishnot grpmax-eligible	25.1%	4
Remaining individualsnot grpmax-eligible	22.7%	4
Middle Eastern	22.3%	4
Ashkenazi Jewishnot grpmax-eligible	20.8%	5
Admixed American	17.9%	6
South Asian	15.8%	6
East Asian	4.79%	21
African / African-American	4.5%	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.Lys3123Arg
Coding: c.9368A>G
MANE Select: NM_020987
dbSNP: rs10821668
Type: single nucleotide variant
Location: chr10:60071513 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 3123: a UniProt-annotated variant site (in)

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.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-lys3123arg (accessed [today's date]).

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