# NM_001039469.3(MARK2):c.645_646insA (p.Ala216fs)

https://sugi.bio/variant/mark2-p-ala216fs

## Summary

**MARK2 p.Ala216fs (c.645_646insA)** is classified **Uncertain significance** in MARK2 (ClinVar, Single submitter, 2 submitters). Associated with autism.

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · 2 linked conditions

## For patients & families {#patients}

This is a change in the MARK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to autism.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1908 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MARK2](https://sugi.bio/atlas/gene/MARK2/) |
| Protein change (HGVS p.) | p.Ala216fs |
| Coding change (HGVS c.) | c.645_646insA |
| MANE Select transcript | [NM_001039469](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039469) |
| Variant type | Insertion |
| Location | chr11:63899987-63899988 (GRCh38) |
| ClinVar | [VCV3900984](https://www.ncbi.nlm.nih.gov/clinvar/variation/3900984/) |

**All HGVS expressions:** `NC_000011.10:g.63899987_63899988insA`, `NC_000011.9:g.63667459_63667460insA`, `NG_029771.1:g.66060_66061insA`, `NM_001039469.3:c.645_646insA`, `NM_001163296.2:c.645_646insA`, `NM_001163297.2:c.645_646insA`, `NM_004954.5:c.645_646insA`, `NM_017490.4:c.546_547insA`

## 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 -8.426, GERP -3.82 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.287, 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 8 of 19**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**MARK2** population constraint: LOEUF 0.287, pLI 1, missense-Z 4.8548. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **216** lies in the protein kinase domain; a UniProt-annotated variant site (in mrd76; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 68.21, 41% of residues very-high.

**5 experimental structure(s)** (PDB): [3IEC](https://www.rcsb.org/structure/3IEC), [5EAK](https://www.rcsb.org/structure/5EAK), [5KZ7](https://www.rcsb.org/structure/5KZ7), [5KZ8](https://www.rcsb.org/structure/5KZ8), [8TXY](https://www.rcsb.org/structure/8TXY).

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

*Describes the biological roles of MARK2 (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:** MARK2's established molecular role includes magnesium ion binding. p.Ala216fs falls in the protein kinase domain.


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

**Molecular function:** magnesium ion binding, RNA binding, protein serine/threonine kinase activity, ATP binding, cadherin binding, tau-protein kinase activity.

**Biological process:** protein phosphorylation, positive regulation of neuron projection development, establishment of cell polarity, intracellular signal transduction, establishment or maintenance of epithelial cell apical/basal polarity, regulation of axonogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Xiaolan Lab, Jiangxi Provincial Children's Hospital | Uncertain significance | criteria provided, single submitter | research |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2025-07-25 |

## Associated conditions {#conditions}

[autism](https://sugi.bio/atlas/disease/autism/), [intellectual developmental disorder, autosomal dominant 76](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-autosomal-dominant-76/).

**Reported phenotype names (ClinVar):** Autism, Intellectual developmental disorder, autosomal dominant 76, Autistic disorder, Autistic disorder of childhood onset.

## Similar variants {#similar}

Related MARK2 variant pages (same residue, condition, or type): [MARK2 p.Ala432Thr](/variant/mark2-p-ala432thr), [MARK2 c.2006+2T>G](/variant/mark2-c-2006-plus-2t-g), [MARK2 c.337+1G>T](/variant/mark2-c-337-plus-1g-t), [MARK2 p.Gly135Arg](/variant/mark2-p-gly135arg), [MARK2 p.Gly580fs](/variant/mark2-p-gly580fs), [MARK2 p.Tyr215Ter](/variant/mark2-p-tyr215ter), [MARK2 p.Tyr267Ter](/variant/mark2-p-tyr267ter), [MARK2 c.1101+5G>A](/variant/mark2-c-1101-plus-5g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3900984). 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.*