Is ANK3 p.Ala3312Val (c.9935C>T) pathogenic?

ANK3 p.Ala3312Val (c.9935C>T) is classified Conflicting classifications of pathogenicity in ANK3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1248); Ultra-rare (popmax 0.0506%, nfe); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

What condition is associated with ANK3 p.Ala3312Val (c.9935C>T)?

ANK3 p.Ala3312Val (c.9935C>T) is associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome (ClinVar).

How common is ANK3 p.Ala3312Val (c.9935C>T) in the general population?

ANK3 p.Ala3312Val (c.9935C>T) is ultra-rare (popmax 0.0506%, nfe) (gnomAD).

What do computational predictors say about ANK3 p.Ala3312Val (c.9935C>T)?

AlphaMissense predicts likely benign (score 0.1248) — an in-silico prediction, not a clinical call.

ANK3 p.Ala3312Val

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.9935C>T · rs201625904 · VCV377485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1248 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

intellectual disability-hypotonia-spasticity-sleep disorder syndrome

Computational evidence

Protein change
AlphaMissense	0.1248	likely benign
REVEL	0.117	moderately 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 8.7	GERP 3.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,360 bp · p 0.0017 · regional, not allelic
Overall
CADD	24.6	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 0.0506% European (non-Finnish) · 597/1,180,000 alleles

Filtering AF 0.0472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.0493% 796/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.7%	18
Finnishnot grpmax-eligible	0.167%	598
European (non-Finnish)grpmax	0.0506%	1,977
Remaining individualsnot grpmax-eligible	0.0288%	3,472
Admixed American	0.0267%	3,750
Middle Eastern	0.0164%	6,082
African / African-American	0.00667%	14,983

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.Ala3312Val
Coding: c.9935C>T
MANE Select: NM_020987
dbSNP: rs201625904
Type: single nucleotide variant
Location: chr10:60070946 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 3312: 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.Ala3312Pro 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-ala3312val (accessed [today's date]).

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