# NM_000037.4(ANK1):c.65C>G (p.Ser22Ter)

https://sugi.bio/variant/ank1-p-ser22ter

## Summary

**ANK1 p.Ser22Ter (c.65C>G)** is classified **Likely pathogenic** in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-24). Absent from gnomAD v4.1; Associated with hereditary spherocytosis type 1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ANK1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hereditary spherocytosis type 1.

*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 (Germany) |
| Diagnostic panels | ANK1 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hereditary spherocytosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Increased red cell osmotic fragility — Very frequent (99-80%)
- Jaundice — Frequent (79-30%)
- Pallor — Frequent (79-30%)
- Cholelithiasis — Frequent (79-30%)
- Muscle weakness — Frequent (79-30%)
- Splenomegaly — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Reticulocytosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024621/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANK1](https://sugi.bio/atlas/gene/ANK1/) |
| Protein change (HGVS p.) | p.Ser22Ter |
| Coding change (HGVS c.) | c.65C>G |
| MANE Select transcript | [NM_000037](https://www.ncbi.nlm.nih.gov/nuccore/NM_000037) |
| Variant type | single nucleotide variant |
| Location | chr8:41758100-41758100 (GRCh38) |
| ClinVar | [VCV4081154](https://www.ncbi.nlm.nih.gov/clinvar/variation/4081154/) |

**All HGVS expressions:** `NC_000008.10:g.41615618G>C`, `NC_000008.11:g.41758100G>C`, `NG_012820.2:g.143663C>G`, `NM_000037.4:c.65C>G`, `NM_001142446.2:c.164C>G`, `NM_020475.3:c.65C>G`, `NM_020476.3:c.65C>G`, `NM_020477.3:c.65C>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.30) — consistent with the pathogenic call
- Conservation: phyloP 11.747, GERP 1.99, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.299, 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 2 of 43**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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}

**ANK1** population constraint: LOEUF 0.299, pLI 1, missense-Z 3.8484. *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):

- **hereditary spherocytosis** — Limited (AR)
- **hereditary spherocytosis** — Definitive (AD)

## Protein context {#protein}

Residue **22** lies in an α-helix; the '89 kda domain' region.

AlphaFold model confidence (whole protein): pLDDT 69.64, 36% of residues very-high.

**21 experimental structure(s)** (PDB): [1N11](https://www.rcsb.org/structure/1N11), [2YQF](https://www.rcsb.org/structure/2YQF), [2YVI](https://www.rcsb.org/structure/2YVI), [3F59](https://www.rcsb.org/structure/3F59), [3KBT](https://www.rcsb.org/structure/3KBT), [3KBU](https://www.rcsb.org/structure/3KBU).

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

*Describes the biological roles of ANK1 (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:** ANK1's established molecular role includes cytoskeletal adaptor activity. p.Ser22Ter falls in the 89 kda domain region.


### Pathways affected {#pathways}

ANK1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [CHL1 interactions](https://reactome.org/content/detail/R-HSA-447041) | electronic |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |
| [Neurofascin interactions](https://reactome.org/content/detail/R-HSA-447043) | electronic |
| [NrCAM interactions](https://reactome.org/content/detail/R-HSA-447038) | electronic |

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

**Molecular function:** cytoskeletal adaptor activity, enzyme binding, protein phosphatase binding, spectrin binding, ATPase binding.

**Biological process:** endoplasmic reticulum to Golgi vesicle-mediated transport, protein localization to plasma membrane.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-24 |

## Associated conditions {#conditions}

[hereditary spherocytosis type 1](https://sugi.bio/atlas/disease/hereditary-spherocytosis-type-1/).

**Reported phenotype names (ClinVar):** Hereditary spherocytosis type 1, Spherocytosis type 1, ANK1-Related Spherocytosis.

## Similar variants {#similar}

Related ANK1 variant pages (same residue, condition, or type): [ANK1 p.Ser22=](/variant/ank1-p-ser22), [ANK1 c.1305+1G>A](/variant/ank1-c-1305-plus-1g-a), [ANK1 c.1405-9G>A](/variant/ank1-c-1405-minus-9g-a), [ANK1 c.1702-2A>G](/variant/ank1-c-1702-minus-2a-g), [ANK1 c.1801-17G>A](/variant/ank1-c-1801-minus-17g-a), [ANK1 c.2296-1G>A](/variant/ank1-c-2296-minus-1g-a), [ANK1 c.2296-2A>G](/variant/ank1-c-2296-minus-2a-g), [ANK1 c.2389-2A>G](/variant/ank1-c-2389-minus-2a-g).

### 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 4081154). 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.*