Is ANK3 p.Arg4089Trp (c.12265C>T) pathogenic?

ANK3 p.Arg4089Trp (c.12265C>T) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.9829); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with ANK3 p.Arg4089Trp (c.12265C>T)?

ANK3 p.Arg4089Trp (c.12265C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANK3 p.Arg4089Trp (c.12265C>T) in the general population?

ANK3 p.Arg4089Trp (c.12265C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about ANK3 p.Arg4089Trp (c.12265C>T)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

ANK3 p.Arg4089Trp

c.12265C>T · rs1241719626 · VCV2182119

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic · top 10% in ANK3
REVEL	0.63	indeterminate
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6.6	GERP 5.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,548 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	29.1	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 0.00401% African / African-American · 3/74,840 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00137% 22/1,609,744 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00642%	15,586
African / African-Americangrpmax	0.00401%	24,947
Admixed American	0.00334%	29,965
European (non-Finnish)	0.0011%	90,518

Remaining individuals 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.Arg4089Trp
Coding: c.12265C>T
MANE Select: NM_020987
dbSNP: rs1241719626
Type: single nucleotide variant
Location: chr10:60067989 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 4089: an α-helix; 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.Arg4089Gln 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-arg4089trp (accessed [today's date]).

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