# NM_001148.6(ANK2):c.3201dup (p.Pro1068fs)

https://sugi.bio/variant/ank2-p-pro1068fs

## Summary

**ANK2 p.Pro1068fs (c.3201dup)** is classified **Likely pathogenic** in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2502464213 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ANK2 gene that is considered likely disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANK2](https://sugi.bio/atlas/gene/ANK2/) |
| Protein change (HGVS p.) | p.Pro1068fs |
| Coding change (HGVS c.) | c.3201dup |
| MANE Select transcript | [NM_001148](https://www.ncbi.nlm.nih.gov/nuccore/NM_001148) |
| dbSNP | [rs2502464213](https://www.ncbi.nlm.nih.gov/snp/rs2502464213/) |
| Variant type | Duplication |
| Location | chr4:113332043-113332044 (GRCh38) |
| ClinVar | [VCV2576797](https://www.ncbi.nlm.nih.gov/clinvar/variation/2576797/) |

**All HGVS expressions:** `LRG_327:g.518965dup`, `LRG_327t1:c.3201dup`, `LRG_327t2:c.3174dup`, `NC_000004.11:g.114253203dup`, `NC_000004.12:g.113332047dup`, `NG_009006.2:g.518965dup`, `NM_001127493.3:c.3174dup`, `NM_001148.6:c.3201dup`, `NM_001354225.2:c.3213dup`, `NM_001354228.2:c.3126-1007dup`, `NM_001354230.2:c.3204-1007dup`, `NM_001354231.2:c.3243dup`, `NM_001354232.2:c.3237dup`, `NM_001354235.2:c.3198dup`, `NM_001354236.2:c.3123-1007dup`, `NM_001354237.2:c.3279dup`, `NM_001354239.2:c.3171dup`, `NM_001354240.2:c.3246dup`, `NM_001354241.2:c.3246dup`, `NM_001354242.2:c.3243dup`, `NM_001354243.2:c.3138dup`, `NM_001354244.2:c.3135dup`, `NM_001354245.2:c.3063-1007dup`, `NM_001354246.2:c.3198dup`, `NM_001354249.2:c.3039-1007dup`, `NM_001354252.2:c.3171dup`, `NM_001354253.2:c.3000-1007dup`, `NM_001354254.2:c.3150dup`, `NM_001354255.2:c.3138dup`, `NM_001354256.2:c.3135dup`, `NM_001354257.2:c.2964-1007dup`, `NM_001354258.2:c.3126-1007dup`, `NM_001354260.2:c.2940-1007dup`, `NM_001354261.2:c.3084-1007dup`, `NM_001354262.2:c.3063-1007dup`, `NM_001354264.2:c.3039-1007dup`, `NM_001354265.2:c.3198dup`, `NM_001354266.2:c.3039-1007dup`, `NM_001354267.2:c.3039-1007dup`, `NM_001354268.2:c.3027-1007dup`, `NM_001354269.3:c.2988dup`, `NM_001354270.2:c.3000-1007dup`, `NM_001354271.2:c.2940-1007dup`, `NM_001354272.2:c.3096-1007dup`, `NM_001354273.2:c.2925-1007dup`, `NM_001354274.2:c.3024-1007dup`, `NM_001354275.2:c.3063-1007dup`, `NM_001354276.2:c.3039-1007dup`, `NM_001354277.2:c.2841-1007dup`, `NM_001354278.2:c.753-1007dup`, `NM_001354279.2:c.789-1007dup`, `NM_001354280.2:c.753-1007dup`, `NM_001354281.2:c.753-1007dup`, `NM_001354282.2:c.789-1007dup`, `NM_001386142.1:c.3024-1007dup`, `NM_001386143.1:c.3138dup`, `NM_001386144.1:c.3246dup`, `NM_001386146.1:c.3039-1007dup`, `NM_001386147.1:c.3084-1007dup`, `NM_001386148.2:c.3186dup`, `NM_001386149.1:c.3039-1007dup`, `NM_001386150.1:c.3039-1007dup`, `NM_001386151.1:c.2940-1007dup`, `NM_001386152.1:c.3258dup`, `NM_001386153.1:c.3039-1007dup`, `NM_001386154.1:c.3024-1007dup`, `NM_001386156.1:c.2964-1007dup`, `NM_001386157.1:c.2841-1007dup`, `NM_001386158.1:c.2742-1007dup`, `NM_001386160.1:c.3069-1007dup`, `NM_001386161.1:c.3135dup`, `NM_001386162.1:c.3039-1007dup`, `NM_001386174.1:c.3342dup`, `NM_001386175.1:c.3318dup`, `NM_001386186.2:c.3186dup`, `NM_001386187.2:c.3090-1007dup`, `NM_020977.5:c.3201dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.915, GERP 2.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.271, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 28 of 46**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ANK2** population constraint: LOEUF 0.271, pLI 1, missense-Z 4.2752; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Definitive (AD)
- **Brugada syndrome** — Disputed (AD)
- **catecholaminergic polymorphic ventricular tachycardia** — Disputed (AD)
- **long QT syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **1068** lies in the zu5 1 domain; the 'interaction with sptbn1' region.

**11 experimental structure(s)** (PDB): [4D8O](https://www.rcsb.org/structure/4D8O), [4RLV](https://www.rcsb.org/structure/4RLV), [4RLY](https://www.rcsb.org/structure/4RLY), [5Y4D](https://www.rcsb.org/structure/5Y4D), [5Y4E](https://www.rcsb.org/structure/5Y4E), [5Y4F](https://www.rcsb.org/structure/5Y4F).

## What this gene does {#gene-function}

*Describes the biological roles of ANK2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ANK2's established molecular role includes enzyme binding. p.Pro1068fs falls in the zu5 1 domain.


### Pathways affected {#pathways}

ANK2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme binding, protein kinase binding, spectrin binding, transmembrane transporter binding, phosphorylation-dependent protein binding.

**Biological process:** regulation of heart rate, atrial septum development, intracellular protein localization, positive regulation of gene expression, regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion, regulation of cardiac muscle contraction by calcium ion signaling.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-16.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-08-16 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related ANK2 variant pages (same residue, condition, or type): [ANK2 c.11695-4dup](/variant/ank2-c-11695-minus-4dup), [ANK2 c.4248+6dup](/variant/ank2-c-4248-plus-6dup), [ANK2 p.Ala1405fs](/variant/ank2-p-ala1405fs), [ANK2 p.Glu1100Ter](/variant/ank2-p-glu1100ter), [ANK2 p.Gly2083fs](/variant/ank2-p-gly2083fs), [ANK2 p.Thr3457fs](/variant/ank2-p-thr3457fs), [ANK2 p.Val1095fs](/variant/ank2-p-val1095fs), [ANK2 c.2685_2693+30dup](/variant/ank2-c-2685-2693-plus-30dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2576797). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*