Is ANK3 p.Thr1015= (c.3045G>T) pathogenic?

ANK3 p.Thr1015= (c.3045G>T) is classified Benign in ANK3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 33.6%, 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.Thr1015= (c.3045G>T)?

ANK3 p.Thr1015= (c.3045G>T) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

ANK3 p.Thr1015=

Q: How common is ANK3 p.Thr1015= (c.3045G>T) in the general population?

ANK3 p.Thr1015= (c.3045G>T) is common (popmax 33.6%, 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.3045G>T · rs3750800 · VCV128368

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 33.6%, nfe) — too common for a highly-penetrant pathogenic allele

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.
REVEL	0.026	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -13
Overall
CADD	1.748	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 33.6% European (non-Finnish) · 396,198/1,179,748 alleles

Filtering AF 33.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.5%

Overall 30.5% 492,812/1,613,664 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	36.3%	3
European (non-Finnish)grpmax	33.6%	3
Finnishnot grpmax-eligible	33%	3
South Asian	32.1%	3
Middle Eastern	29.8%	3
Remaining individualsnot grpmax-eligible	29.1%	3
Ashkenazi Jewishnot grpmax-eligible	27.1%	4
Admixed American	17.2%	6
East Asian	7.18%	14
African / African-American	5.88%	17

Amish 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.Thr1015=
Coding: c.3045G>T
MANE Select: NM_020987
dbSNP: rs3750800
Type: single nucleotide variant
Location: chr10:60108958 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 1015: the zu5 1 domain

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.Thr1015Met Uncertain significance ★ 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
ANK3 p.Arg852His 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-thr1015 (accessed [today's date]).

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