Is ANK3 p.Leu1328= (c.3984G>A) pathogenic?

ANK3 p.Leu1328= (c.3984G>A) is classified Benign/Likely benign in ANK3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-01). Low-frequency (popmax 1.21%, afr); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Leu1328= (c.3984G>A)?

ANK3 p.Leu1328= (c.3984G>A) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Leu1328= (c.3984G>A) in the general population?

ANK3 p.Leu1328= (c.3984G>A) is low-frequency (popmax 1.21%, afr) (gnomAD).

ANK3 p.Leu1328=

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.3984G>A · rs149052618 · VCV713120

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.21%, afr)

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 0.37	GERP 1.1, phastCons 0.99
Overall
CADD	11.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.21% African / African-American · 908/75,004 alleles

Filtering AF 1.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.12%

Overall 0.0638% 1,030/1,613,852 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.21%	83
Remaining individualsnot grpmax-eligible	0.0848%	1,179
Admixed American	0.0834%	1,199
Middle Eastern	0.033%	3,030
South Asian	0.00659%	15,172
European (non-Finnish)	0.000932%	107,265

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.Leu1328=
Coding: c.3984G>A
MANE Select: NM_020987
dbSNP: rs149052618
Type: single nucleotide variant
Location: chr10:60084692 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 1328: the 'upa domain' 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-leu1328 (accessed [today's date]).

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