Is ANK3 p.Thr3595Ala (c.10783A>G) pathogenic?

ANK3 p.Thr3595Ala (c.10783A>G) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.518); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ANK3 p.Thr3595Ala (c.10783A>G)?

ANK3 p.Thr3595Ala (c.10783A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANK3 p.Thr3595Ala (c.10783A>G) in the general population?

ANK3 p.Thr3595Ala (c.10783A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ANK3 p.Thr3595Ala (c.10783A>G)?

AlphaMissense predicts ambiguous (score 0.518) — an in-silico prediction, not a clinical call.

ANK3 p.Thr3595Ala

c.10783A>G · rs748256287 · VCV1047226

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.518	ambiguous
REVEL	0.349	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 5.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,360 bp · p 0.0017 · regional, not allelic
Overall
CADD	23.8	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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,822 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
European (non-Finnish)	8.47e-05%	1,179,990

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.Thr3595Ala
Coding: c.10783A>G
MANE Select: NM_020987
dbSNP: rs748256287
Type: single nucleotide variant
Location: chr10:60070098 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 3595: 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

Similar variants

ANK3 p.Thr3595Ile Uncertain significance ★ same residue
ANK3 p.Ala1534Val 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
ANK3 p.Arg1012Cys 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-thr3595ala (accessed [today's date]).

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