# NM_020987.5(ANK3):c.6571C>G (p.Pro2191Ala)

https://sugi.bio/variant/ank3-p-pro2191ala

## Summary

**ANK3 p.Pro2191Ala (c.6571C>G)** is classified **Uncertain significance** in ANK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.0687); Ultra-rare (popmax 0.025%, amr); Associated with intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs140516425 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.025%, amr)

## 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 intellectual disability-hypotonia-spasticity-sleep disorder syndrome.

*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 recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | ANK3 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of ANK3-related intellectual disability-sleep disturbance syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Aggressive behavior — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Hyperactivity — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Intellectual disability, moderate — Frequent (79-30%)
- Sleep abnormality — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017541/index) · [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.Pro2191Ala |
| Coding change (HGVS c.) | c.6571C>G |
| MANE Select transcript | [NM_020987](https://www.ncbi.nlm.nih.gov/nuccore/NM_020987) |
| dbSNP | [rs140516425](https://www.ncbi.nlm.nih.gov/snp/rs140516425/) |
| Variant type | single nucleotide variant |
| Location | chr10:60074310-60074310 (GRCh38) |
| ClinVar | [VCV1408246](https://www.ncbi.nlm.nih.gov/clinvar/variation/1408246/) |

**All HGVS expressions:** `NC_000010.10:g.61834068G>C`, `NC_000010.11:g.60074310G>C`, `NG_029917.1:g.664217C>G`, `NM_001149.4:c.1807+6227C>G`, `NM_001204403.2:c.4387+6227C>G`, `NM_001204404.2:c.4408+6227C>G`, `NM_001320874.2:c.4405+6227C>G`, `NM_020987.5:c.6571C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0687)
- REVEL 0.157 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- Conservation: phyloP 9.944, GERP 5.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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 0.92** across the covering region of the MANE Select transcript (60,070,087–60,074,447), spanning 4,360 bp. Chi-square p 0.0017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **0.025%** (amr) · FAF95 0.0154% · FAF99 0.0124% · 15/59,978 in the highest group · 161/1,613,888 alleles overall — ultra-rare (popmax 0.025%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.025% | 3,999 |
| European (non-Finnish) | 0.0112% | 8,939 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,496 |
| South Asian | 0.00439% | 22,764 |
| African / African-American | 0.00401% | 24,957 |
| East Asian | 0.00223% | 44,876 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |

*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 **2191** 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.Pro2191Ala 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-26.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Daryl Scott Lab, Baylor College of Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-26 |

## Associated conditions {#conditions}

[intellectual disability-hypotonia-spasticity-sleep disorder syndrome](https://sugi.bio/atlas/disease/intellectual-disability-hypotonia-spasticity-sleep-disorder-syndrome/).

**Reported phenotype names (ClinVar):** Intellectual disability-hypotonia-spasticity-sleep disorder syndrome, not provided, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 37, none provided.

## Similar variants {#similar}

Related ANK3 variant pages (same residue, condition, or type): [ANK3 p.Ala1630Val](/variant/ank3-p-ala1630val), [ANK3 p.Ala2023Thr](/variant/ank3-p-ala2023thr), [ANK3 p.Ala628Thr](/variant/ank3-p-ala628thr), [ANK3 p.Arg1243His](/variant/ank3-p-arg1243his), [ANK3 p.Arg1575Trp](/variant/ank3-p-arg1575trp), [ANK3 p.Arg2239Cys](/variant/ank3-p-arg2239cys), [ANK3 p.Arg852His](/variant/ank3-p-arg852his), [ANK3 p.Asn224Ser](/variant/ank3-p-asn224ser).

### 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 1408246). 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.*