Is ANK2 p.Ala1405fs (c.4212dup) pathogenic?

ANK2 p.Ala1405fs (c.4212dup) is classified Pathogenic in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). Very rare (popmax 0.00167%, amr); Associated with long QT syndrome.

What condition is associated with ANK2 p.Ala1405fs (c.4212dup)?

ANK2 p.Ala1405fs (c.4212dup) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Ala1405fs (c.4212dup) in the general population?

ANK2 p.Ala1405fs (c.4212dup) is very rare (popmax 0.00167%, amr) (gnomAD).

ANK2 p.Ala1405fs

c.4212dup · VCV4732021

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

long QT syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 34 of 46
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000657% 1/152,192 alleles · very rare

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: ANK2
Protein: p.Ala1405fs
Coding: c.4212dup
MANE Select: NM_001148
Type: Duplication
Location: chr4:113343099 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1405: the 'upa domain' region

Full ANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANK2 p.Ala1405Thr Uncertain significance ★ same residue
ANK2 c.11695-4dup Likely benign ★★ same condition
ANK2 c.4248+6dup Likely benign ★★ same condition
ANK2 p.Thr3371_Val3372insLysThr Uncertain significance ★ same condition
ANK2 c.11032+4_11032+7dup Likely benign ★ same condition
ANK2 c.4122+15dup Benign ★ same condition
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 p.Gln3921Ter Pathogenic ★★ 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/ank2-p-ala1405fs (accessed [today's date]).

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