# NM_001148.6(ANK2):c.5240C>G (p.Pro1747Arg)

https://sugi.bio/variant/ank2-p-pro1747arg

## Summary

**ANK2 p.Pro1747Arg (c.5240C>G)** is classified **Likely benign** in ANK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.16); Rare (popmax 0.172%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs200628845 · 6 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.172%, amr)

## For patients & families {#patients}

This is a change in the ANK2 gene that is classified as likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to Cardiovascular phenotype.

*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.Pro1747Arg |
| Coding change (HGVS c.) | c.5240C>G |
| dbSNP | [rs200628845](https://www.ncbi.nlm.nih.gov/snp/rs200628845/) |
| Variant type | single nucleotide variant |
| Location | chr4:113353858-113353858 (GRCh38) |
| ClinVar | [VCV263614](https://www.ncbi.nlm.nih.gov/clinvar/variation/263614/) |

**All HGVS expressions:** `LRG_327:g.540776C>G`, `LRG_327t1:c.5240C>G`, `NC_000004.11:g.114275014C>G`, `NC_000004.12:g.113353858C>G`, `NG_009006.2:g.540776C>G`, `NM_001127493.3:c.4399+3609C>G`, `NM_001148.6:c.5240C>G`, `NM_001354225.2:c.4438+3609C>G`, `NM_001354228.2:c.4327+3609C>G`, `NM_001354230.2:c.4405+3609C>G`, `NM_001354231.2:c.4468+3609C>G`, `NM_001354232.2:c.4462+3609C>G`, `NM_001354235.2:c.4423+3609C>G`, `NM_001354236.2:c.4324+3609C>G`, `NM_001354237.2:c.4504+3609C>G`, `NM_001354239.2:c.4396+3609C>G`, `NM_001354240.2:c.4471+3609C>G`, `NM_001354241.2:c.4471+3609C>G`, `NM_001354242.2:c.4468+3609C>G`, `NM_001354243.2:c.4363+3609C>G`, `NM_001354244.2:c.4360+3609C>G`, `NM_001354245.2:c.4264+3609C>G`, `NM_001354246.2:c.4423+3609C>G`, `NM_001354249.2:c.4240+3609C>G`, `NM_001354252.2:c.4396+3609C>G`, `NM_001354253.2:c.4201+3609C>G`, `NM_001354254.2:c.4375+3609C>G`, `NM_001354255.2:c.4363+3609C>G`, `NM_001354256.2:c.4360+3609C>G`, `NM_001354257.2:c.4165+3609C>G`, `NM_001354258.2:c.4327+3609C>G`, `NM_001354260.2:c.4141+3609C>G`, `NM_001354261.2:c.4285+3609C>G`, `NM_001354262.2:c.4264+3609C>G`, `NM_001354264.2:c.4261+3609C>G`, `NM_001354265.2:c.4423+3609C>G`, `NM_001354266.2:c.4240+3609C>G`, `NM_001354267.2:c.4240+3609C>G`, `NM_001354268.2:c.4228+3609C>G`, `NM_001354269.3:c.4213+3609C>G`, `NM_001354270.2:c.4201+3609C>G`, `NM_001354271.2:c.4141+3609C>G`, `NM_001354272.2:c.4297+3609C>G`, `NM_001354273.2:c.4126+3609C>G`, `NM_001354274.2:c.4192+3609C>G`, `NM_001354275.2:c.4264+3609C>G`, `NM_001354276.2:c.4240+3609C>G`, `NM_001354277.2:c.4042+3609C>G`, `NM_001354278.2:c.1954+3609C>G`, `NM_001354279.2:c.1990+3609C>G`, `NM_001354280.2:c.1975+3609C>G`, `NM_001354281.2:c.1954+3609C>G`, `NM_001354282.2:c.1990+3609C>G`, `NM_001386142.1:c.5006C>G`, `NM_001386143.1:c.4363+3609C>G`, `NM_001386144.1:c.4471+3609C>G`, `NM_001386146.1:c.4207+3609C>G`, `NM_001386147.1:c.4252+3609C>G`, `NM_001386148.2:c.4411+3609C>G`, `NM_001386149.1:c.4207+3609C>G`, `NM_001386150.1:c.4207+3609C>G`, `NM_001386151.1:c.4141+3609C>G`, `NM_001386152.1:c.4483+3609C>G`, `NM_001386153.1:c.4207+3609C>G`, `NM_001386154.1:c.4192+3609C>G`, `NM_001386156.1:c.4165+3609C>G`, `NM_001386157.1:c.4042+3609C>G`, `NM_001386158.1:c.3943+3609C>G`, `NM_001386160.1:c.4270+3609C>G`, `NM_001386161.1:c.4360+3609C>G`, `NM_001386162.1:c.4240+3609C>G`, `NM_001386166.1:c.1640C>G`, `NM_001386167.1:c.826+3609C>G`, `NM_001386174.1:c.5381C>G`, `NM_001386175.1:c.5357C>G`, `NM_001386186.2:c.4411+3609C>G`, `NM_001386187.2:c.4291+3609C>G`, `NM_020977.5:c.4426+3609C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.16)
- REVEL 0.14 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- Conservation: phyloP 6, GERP 2.71, phastCons 0.821 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.0**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (113,353,662–113,381,468), spanning 27,806 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.172%** (amr) · FAF95 0.145% · FAF99 0.135% · 103/59,988 in the highest group · 187/1,613,974 alleles overall — rare (popmax 0.172%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.172% | 582 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0608% | 1,644 |
| Middle Eastern | 0.0165% | 6,058 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,812 |
| South Asian | 0.011% | 9,105 |
| European (non-Finnish) | 0.00398% | 25,106 |

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-20.

**Submitter consensus:** unanimous (6/6 Likely benign).

**Submission history:** 6 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-09 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-14 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-02-04 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-04-27 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [long QT syndrome](https://sugi.bio/atlas/disease/long-qt-syndrome/), [cardiac arrhythmia, ankyrin-B-related](https://sugi.bio/atlas/disease/cardiac-arrhythmia-ankyrin-b-related/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Long QT syndrome, not specified, Cardiac arrhythmia, ankyrin-B-related, not provided, AllHighlyPenetrant, none provided, ANKYRIN-B SYNDROME.

### 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 263614). 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.*