Is ANK3 p.Pro2188Gln (c.6563C>A) pathogenic?

ANK3 p.Pro2188Gln (c.6563C>A) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-12). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.035%, amr); Associated with Inborn genetic diseases.

What condition is associated with ANK3 p.Pro2188Gln (c.6563C>A)?

ANK3 p.Pro2188Gln (c.6563C>A) is associated with Inborn genetic diseases, intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Pro2188Gln (c.6563C>A) in the general population?

ANK3 p.Pro2188Gln (c.6563C>A) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about ANK3 p.Pro2188Gln (c.6563C>A)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

ANK3 p.Pro2188Gln

c.6563C>A · rs190303926 · VCV1506093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.9	GERP 5.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,360 bp · p 0.0017 · regional, not allelic
Overall
CADD	24.0	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 0.035% Admixed American · 21/59,996 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0044% 71/1,613,980 alleles · ultra-rare exomes 52/1,461,726 · genomes 19/152,254 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.877%	114
Admixed Americangrpmax	0.035%	2,857
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00667%	15,002
European (non-Finnish)	0.00237%	42,142
South Asian	0.0011%	91,042

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.Pro2188Gln
Coding: c.6563C>A
MANE Select: NM_020987
dbSNP: rs190303926
Type: single nucleotide variant
Location: chr10:60074318 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 2188: the 'disordered' region

Full ANK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Similar variants

ANK3 p.Ala1534Val Uncertain significance ★★ same condition
ANK3 p.Ala1630Val Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala2023Thr Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala218Thr Uncertain significance ★★ same condition
ANK3 p.Ala259Thr Uncertain significance ★★ same condition
ANK3 p.Ala324Gly Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala3262Val Uncertain significance ★★ ⚠ same condition
ANK3 p.Ala540Thr 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-pro2188gln (accessed [today's date]).

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