# NM_001148.6(ANK2):c.3019C>T (p.Arg1007Ter)

https://sugi.bio/variant/ank2-p-arg1007ter

## Summary

**ANK2 p.Arg1007Ter (c.3019C>T)** is classified **Pathogenic/Likely pathogenic** in ANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-26). Absent from gnomAD v4.1; Associated with cardiac arrhythmia, ankyrin-B-related.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2092061253 · 3 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ANK2 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to cardiac arrhythmia, ankyrin-B-related.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | ANK2 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Romano-Ward syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prolonged QTc interval — Obligate (100%)
- Syncope — Frequent (79-30%)
- Sinus bradycardia — Frequent (79-30%)
- Abnormal T-wave — Frequent (79-30%)
- Seizure — Occasional (29-5%)
- Sudden cardiac death — Occasional (29-5%)
- Torsade de pointes — Occasional (29-5%)
- Ventricular arrhythmia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013294/index) · [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.Arg1007Ter |
| Coding change (HGVS c.) | c.3019C>T |
| MANE Select transcript | [NM_001148](https://www.ncbi.nlm.nih.gov/nuccore/NM_001148) |
| dbSNP | [rs2092061253](https://www.ncbi.nlm.nih.gov/snp/rs2092061253/) |
| Variant type | single nucleotide variant |
| Location | chr4:113330364-113330364 (GRCh38) |
| ClinVar | [VCV985758](https://www.ncbi.nlm.nih.gov/clinvar/variation/985758/) |

**All HGVS expressions:** `LRG_327:g.517282C>T`, `LRG_327t1:c.3019C>T`, `NC_000004.11:g.114251520C>T`, `NC_000004.12:g.113330364C>T`, `NG_009006.2:g.517282C>T`, `NM_001127493.3:c.2992C>T`, `NM_001148.6:c.3019C>T`, `NM_001354225.2:c.3031C>T`, `NM_001354228.2:c.3019C>T`, `NM_001354230.2:c.3097C>T`, `NM_001354231.2:c.3061C>T`, `NM_001354232.2:c.3055C>T`, `NM_001354235.2:c.3016C>T`, `NM_001354236.2:c.3016C>T`, `NM_001354237.2:c.3097C>T`, `NM_001354239.2:c.2989C>T`, `NM_001354240.2:c.3064C>T`, `NM_001354241.2:c.3064C>T`, `NM_001354242.2:c.3061C>T`, `NM_001354243.2:c.2956C>T`, `NM_001354244.2:c.2953C>T`, `NM_001354245.2:c.2956C>T`, `NM_001354246.2:c.3016C>T`, `NM_001354249.2:c.2932C>T`, `NM_001354252.2:c.2989C>T`, `NM_001354253.2:c.2893C>T`, `NM_001354254.2:c.2968C>T`, `NM_001354255.2:c.2956C>T`, `NM_001354256.2:c.2953C>T`, `NM_001354257.2:c.2857C>T`, `NM_001354258.2:c.3019C>T`, `NM_001354260.2:c.2833C>T`, `NM_001354261.2:c.2977C>T`, `NM_001354262.2:c.2956C>T`, `NM_001354264.2:c.2932C>T`, `NM_001354265.2:c.3016C>T`, `NM_001354266.2:c.2932C>T`, `NM_001354267.2:c.2932C>T`, `NM_001354268.2:c.2920C>T`, `NM_001354269.3:c.2806C>T`, `NM_001354270.2:c.2893C>T`, `NM_001354271.2:c.2833C>T`, `NM_001354272.2:c.2989C>T`, `NM_001354273.2:c.2818C>T`, `NM_001354274.2:c.2917C>T`, `NM_001354275.2:c.2956C>T`, `NM_001354276.2:c.2932C>T`, `NM_001354277.2:c.2734C>T`, `NM_001354278.2:c.646C>T`, `NM_001354279.2:c.682C>T`, `NM_001354280.2:c.646C>T`, `NM_001354281.2:c.646C>T`, `NM_001354282.2:c.682C>T`, `NM_001386142.1:c.2917C>T`, `NM_001386143.1:c.2956C>T`, `NM_001386144.1:c.3064C>T`, `NM_001386146.1:c.2932C>T`, `NM_001386147.1:c.2977C>T`, `NM_001386148.2:c.3004C>T`, `NM_001386149.1:c.2932C>T`, `NM_001386150.1:c.2932C>T`, `NM_001386151.1:c.2833C>T`, `NM_001386152.1:c.3076C>T`, `NM_001386153.1:c.2932C>T`, `NM_001386154.1:c.2917C>T`, `NM_001386156.1:c.2857C>T`, `NM_001386157.1:c.2734C>T`, `NM_001386158.1:c.2635C>T`, `NM_001386160.1:c.2962C>T`, `NM_001386161.1:c.2953C>T`, `NM_001386162.1:c.2932C>T`, `NM_001386174.1:c.3160C>T`, `NM_001386175.1:c.3136C>T`, `NM_001386186.2:c.3004C>T`, `NM_001386187.2:c.2983C>T`, `NM_020977.5:c.3019C>T`

## 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 3.987, GERP 1.61, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 27 of 46**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **1007** lies in a β-strand; 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.Arg1007Ter 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-26.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2017–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-26 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-11-17 |
| MGZ Medical Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-25 |

## Associated conditions {#conditions}

[cardiac arrhythmia, ankyrin-B-related](https://sugi.bio/atlas/disease/cardiac-arrhythmia-ankyrin-b-related/).

**Reported phenotype names (ClinVar):** Cardiac arrhythmia, ankyrin-B-related, Inborn genetic diseases, not provided, none provided, ANKYRIN-B SYNDROME.

## Similar variants {#similar}

Related ANK2 variant pages (same residue, condition, or type): [ANK2 p.Arg1007Gln](/variant/ank2-p-arg1007gln), [ANK2 p.Arg1088Ter](/variant/ank2-p-arg1088ter), [ANK2 c.11032+11G>T](/variant/ank2-c-11032-plus-11g-t), [ANK2 c.2900+5141G>A](/variant/ank2-c-2900-plus-5141g-a), [ANK2 c.*1950C>A](/variant/ank2-c-star-1950c-a), [ANK2 p.Ala178Val](/variant/ank2-p-ala178val), [ANK2 p.Ala3485Thr](/variant/ank2-p-ala3485thr), [ANK2 p.Ala373Val](/variant/ank2-p-ala373val).

### 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 985758). 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.*