# NM_020987.5(ANK3):c.1047C>T (p.Cys349=)

https://sugi.bio/variant/ank3-p-cys349

## Summary

**ANK3 p.Cys349= (c.1047C>T)** is classified **Benign/Likely benign** in ANK3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-01). Rare (popmax 0.792%, mid).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs117138204 · 4 submitters · rare (popmax 0.792%, mid)

## For patients & families {#patients}

This is a change in the ANK3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters.

*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.Cys349= |
| Coding change (HGVS c.) | c.1047C>T |
| MANE Select transcript | [NM_020987](https://www.ncbi.nlm.nih.gov/nuccore/NM_020987) |
| dbSNP | [rs117138204](https://www.ncbi.nlm.nih.gov/snp/rs117138204/) |
| Variant type | single nucleotide variant |
| Location | chr10:60208183-60208183 (GRCh38) |
| ClinVar | [VCV210139](https://www.ncbi.nlm.nih.gov/clinvar/variation/210139/) |

**All HGVS expressions:** `NC_000010.10:g.61967941G>A`, `NC_000010.11:g.60208183G>A`, `NG_029917.1:g.530344C>T`, `NM_001204403.2:c.1029C>T`, `NM_001204404.2:c.996C>T`, `NM_001320874.2:c.1047C>T`, `NM_020987.5:c.1047C>T`

## Computational & population evidence {#evidence}

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

- **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 -1.058, GERP -4.22 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.824**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.22 acceptor 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 **0.792%** (mid) · FAF95 0.663% · FAF99 0.658% · 48/6,062 in the highest group · 10,231/1,614,104 alleles overall — rare (popmax 0.792%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.12% | 47 |
| Remaining individuals (not grpmax-eligible) | 0.806% | 124 |
| Middle Eastern (grpmax) | 0.792% | 126 |
| European (non-Finnish) | 0.675% | 148 |
| Admixed American | 0.55% | 182 |
| African / African-American | 0.43% | 232 |
| Finnish (not grpmax-eligible) | 0.3% | 334 |
| South Asian | 0.26% | 384 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


**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.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (2 Benign, 2 Likely benign).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2018-01-19 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |

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

## Similar variants {#similar}

Related ANK3 variant pages (same residue, condition, or type): [ANK3 c.2382+6C>T](/variant/ank3-c-2382-plus-6c-t), [ANK3 p.Ala1461Thr](/variant/ank3-p-ala1461thr), [ANK3 p.Ala1534Val](/variant/ank3-p-ala1534val), [ANK3 p.Ala1630Val](/variant/ank3-p-ala1630val), [ANK3 p.Ala169Thr](/variant/ank3-p-ala169thr), [ANK3 p.Ala2023Thr](/variant/ank3-p-ala2023thr), [ANK3 p.Ala218Thr](/variant/ank3-p-ala218thr), [ANK3 p.Ala2223Thr](/variant/ank3-p-ala2223thr).

### 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 210139). 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.*