# NM_020987.5(ANK3):c.3034C>T (p.Arg1012Cys)

https://sugi.bio/variant/ank3-p-arg1012cys

## Summary

**ANK3 p.Arg1012Cys (c.3034C>T)** is classified **Uncertain significance** in ANK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9532); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2132095747 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ANK3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Arg1012Cys |
| Coding change (HGVS c.) | c.3034C>T |
| MANE Select transcript | [NM_020987](https://www.ncbi.nlm.nih.gov/nuccore/NM_020987) |
| dbSNP | [rs2132095747](https://www.ncbi.nlm.nih.gov/snp/rs2132095747/) |
| Variant type | single nucleotide variant |
| Location | chr10:60108969-60108969 (GRCh38) |
| ClinVar | [VCV2363573](https://www.ncbi.nlm.nih.gov/clinvar/variation/2363573/) |

**All HGVS expressions:** `NC_000010.10:g.61868727G>A`, `NC_000010.11:g.60108969G>A`, `NG_029917.1:g.629558C>T`, `NM_001149.4:c.436C>T`, `NM_001204403.2:c.3016C>T`, `NM_001204404.2:c.3037C>T`, `NM_001320874.2:c.3034C>T`, `NM_020987.5:c.3034C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9532)
- REVEL 0.522 (indeterminate)
- Conservation: phyloP 11.919, GERP 6.46, phastCons 1 — highly conserved (agrees)
- 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.*
- Regional missense constraint: **o/e 0.75** across the covering region of the MANE Select transcript (60,082,158–60,186,715), spanning 104,557 bp. Chi-square p 5.9e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.81 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,966 in the highest group · 1/152,178 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **1012** lies in the zu5 1 domain.

**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.Arg1012Cys falls in the zu5 1 domain.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-31.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-31 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related ANK3 variant pages (same residue, condition, or type): [ANK3 p.Ala1534Val](/variant/ank3-p-ala1534val), [ANK3 p.Ala218Thr](/variant/ank3-p-ala218thr), [ANK3 p.Ala259Thr](/variant/ank3-p-ala259thr), [ANK3 p.Ala324Gly](/variant/ank3-p-ala324gly), [ANK3 p.Ala3262Val](/variant/ank3-p-ala3262val), [ANK3 p.Ala540Thr](/variant/ank3-p-ala540thr), [ANK3 p.Arg1623Gln](/variant/ank3-p-arg1623gln), [ANK3 p.Arg2367Gln](/variant/ank3-p-arg2367gln).

### 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 2363573). 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.*