Is ANK3 p.Arg4369Gln (c.13106G>A) pathogenic?

ANK3 p.Arg4369Gln (c.13106G>A) is classified Benign/Likely benign in ANK3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.246); Low-frequency (popmax 1.32%, mid); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Arg4369Gln (c.13106G>A)?

ANK3 p.Arg4369Gln (c.13106G>A) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Arg4369Gln (c.13106G>A) in the general population?

ANK3 p.Arg4369Gln (c.13106G>A) is low-frequency (popmax 1.32%, mid) (gnomAD).

What do computational predictors say about ANK3 p.Arg4369Gln (c.13106G>A)?

AlphaMissense predicts likely benign (score 0.246) — an in-silico prediction, not a clinical call.

ANK3 p.Arg4369Gln

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.13106G>A · rs141939315 · VCV434147

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.246 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.32%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.246	likely benign
REVEL	0.207	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.35 · regional, not allelic
Overall
CADD	28.4	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 1.32% Middle Eastern · 80/6,062 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1%

Overall 0.637% 10,280/1,613,858 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.96%	51
Middle Easterngrpmax	1.32%	76
European (non-Finnish)	0.679%	147
Remaining individualsnot grpmax-eligible	0.648%	154
South Asian	0.582%	172
Admixed American	0.55%	182
Finnishnot grpmax-eligible	0.286%	350
African / African-American	0.207%	483
East Asian	0.00223%	44,874

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg4369Gln
Coding: c.13106G>A
MANE Select: NM_020987
dbSNP: rs141939315
Type: single nucleotide variant
Location: chr10:60042719 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 4369: 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.Arg4369Trp Uncertain significance ★ same residue
ANK3 p.Arg4369= Likely benign ★ 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

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-arg4369gln (accessed [today's date]).

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