Is ANK3 p.Ile406= (c.1218T>C) pathogenic?

ANK3 p.Ile406= (c.1218T>C) is classified Benign in ANK3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Common (popmax 18.6%, afr) — too common for a highly-penetrant pathogenic allele.

ANK3 p.Ile406=

Q: How common is ANK3 p.Ile406= (c.1218T>C) in the general population?

ANK3 p.Ile406= (c.1218T>C) is common (popmax 18.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1218T>C · rs2297979 · VCV128362

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 18.6%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.044	GERP -3.9, phastCons 0.081
Overall
CADD	5.534	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.6% African / African-American · 13,948/74,926 alleles

Filtering AF 18.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.3%

Overall 17.5% 281,983/1,611,316 alleles · common exomes 255,753/1,459,124 · genomes 26,230/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.6%	5
European (non-Finnish)	18.3%	5
Ashkenazi Jewishnot grpmax-eligible	17.9%	6
Remaining individualsnot grpmax-eligible	17.5%	6
South Asian	17%	6
Middle Eastern	14.8%	7
Finnishnot grpmax-eligible	14.7%	7
Admixed American	14%	7
Amishnot grpmax-eligible	13.5%	7
East Asian	5.33%	19

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.Ile406=
Coding: c.1218T>C
MANE Select: NM_020987
dbSNP: rs2297979
Type: single nucleotide variant
Location: chr10:60205867 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)

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

Similar variants

ANK3 c.2382+6C>T Uncertain significance ★★ same type
ANK3 p.Ala1461Thr Uncertain significance ★★ ⚠ same type
ANK3 p.Ala1534Val Uncertain significance ★★ same type
ANK3 p.Ala1630Val Uncertain significance ★★ ⚠ same type
ANK3 p.Ala169Thr Uncertain significance ★★ same type
ANK3 p.Ala2023Thr Uncertain significance ★★ ⚠ same type
ANK3 p.Ala218Thr Uncertain significance ★★ same type
ANK3 p.Ala2223Thr Uncertain significance ★★ ⚠ same type

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-ile406 (accessed [today's date]).

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