Is ANK3 p.Ser4342Arg (c.13024A>C) pathogenic?

ANK3 p.Ser4342Arg (c.13024A>C) is classified Uncertain significance in ANK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-18). AlphaMissense: likely benign (0.2381); Very rare (popmax 0.00549%, sas); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Ser4342Arg (c.13024A>C)?

ANK3 p.Ser4342Arg (c.13024A>C) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Ser4342Arg (c.13024A>C) in the general population?

ANK3 p.Ser4342Arg (c.13024A>C) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about ANK3 p.Ser4342Arg (c.13024A>C)?

AlphaMissense predicts likely benign (score 0.2381) — an in-silico prediction, not a clinical call.

ANK3 p.Ser4342Arg

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.13024A>C · rs775338026 · VCV1329490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.2381	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.35 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,072 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,614,070 alleles · very rare exomes 8/1,461,732 · genomes 1/152,338 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,214
Remaining individualsnot grpmax-eligible	0.0048%	20,833
East Asian	0.00223%	44,872

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.Ser4342Arg
Coding: c.13024A>C
MANE Select: NM_020987
dbSNP: rs775338026
Type: single nucleotide variant
Location: chr10:60055699 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 4342: the 'disordered' region

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-ser4342arg (accessed [today's date]).

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