# NM_020987.5(ANK3):c.93del (p.Ser32fs)

https://sugi.bio/variant/ank3-p-ser32fs

## Summary

**ANK3 p.Ser32fs (c.93del)** is classified **Pathogenic** in ANK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). Very rare (popmax 0.00223%, eas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs759973241 · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ANK3 gene that is reported as disease-causing, but on limited review, 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 | [ANK3](https://sugi.bio/atlas/gene/ANK3/) |
| Protein change (HGVS p.) | p.Ser32fs |
| Coding change (HGVS c.) | c.93del |
| MANE Select transcript | [NM_020987](https://www.ncbi.nlm.nih.gov/nuccore/NM_020987) |
| dbSNP | [rs759973241](https://www.ncbi.nlm.nih.gov/snp/rs759973241/) |
| Variant type | Deletion |
| Location | chr10:60389446-60389446 (GRCh38) |
| ClinVar | [VCV1455955](https://www.ncbi.nlm.nih.gov/clinvar/variation/1455955/) |

**All HGVS expressions:** `NC_000010.10:g.62149205del`, `NC_000010.11:g.60389447del`, `NG_029917.1:g.349081del`, `NM_001204403.2:c.97-109807del`, `NM_001204404.2:c.64-109807del`, `NM_001320874.2:c.93del`, `NM_020987.5:c.93del`

## 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 11.203, GERP 2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.16, 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 1 of 44**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,884 in the highest group · 5/1,613,666 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,884 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,472 |
| European (non-Finnish) | 0.000254% | 393,306 |

*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}

**ANK3** population constraint: LOEUF 0.16, pLI 1, missense-Z 5.3717. *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):

- **intellectual disability** — Moderate (AR)

## Protein context {#protein}

Residue **32** lies in the 'disordered' region.

**1 experimental structure(s)** (PDB): [4O6X](https://www.rcsb.org/structure/4O6X).

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

*Describes the biological roles of ANK3 (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:** ANK3's established molecular role includes structural constituent of cytoskeleton. p.Ser32fs falls in the disordered region.


### Pathways affected {#pathways}

ANK3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |

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

**Molecular function:** structural constituent of cytoskeleton.

**Biological process:** mitotic cytokinesis, plasma membrane organization, Golgi to plasma membrane protein transport, establishment of protein localization, membrane assembly, protein localization to plasma membrane.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-10.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ANK3 variant pages (same residue, condition, or type): [ANK3 p.Arg1456fs](/variant/ank3-p-arg1456fs), [ANK3 p.Glu4256_Ile4257delinsVal](/variant/ank3-p-glu4256-ile4257delinsval), [ANK3 c.2614+6del](/variant/ank3-c-2614-plus-6del), [ANK3 c.4351-10del](/variant/ank3-c-4351-minus-10del), [ANK3 c.212_216+1del](/variant/ank3-c-212-216-plus-1del), [ANK3 p.Ala1197fs](/variant/ank3-p-ala1197fs), [ANK3 p.Ala622fs](/variant/ank3-p-ala622fs), [ANK3 p.Asp1271fs](/variant/ank3-p-asp1271fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1455955). 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.*