# NM_001039469.3(MARK2):c.1181dup (p.Val395fs)

https://sugi.bio/variant/mark2-p-val395fs

## Summary

**MARK2 p.Val395fs (c.1181dup)** is classified **Pathogenic** in MARK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-03). No gnomAD frequency available for this variant; Associated with autism spectrum disorder.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2539326870 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MARK2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to autism spectrum disorder.

*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 | 1576 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.Val395fs |
| Coding change (HGVS c.) | c.1181dup |
| MANE Select transcript | [NM_001039469](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039469) |
| dbSNP | [rs2539326870](https://www.ncbi.nlm.nih.gov/snp/rs2539326870/) |
| Variant type | Duplication |
| Location | chr11:63902275-63902276 (GRCh38) |
| ClinVar | [VCV3253629](https://www.ncbi.nlm.nih.gov/clinvar/variation/3253629/) |

**All HGVS expressions:** `NC_000011.10:g.63902277dup`, `NC_000011.9:g.63669749dup`, `NG_029771.1:g.68350dup`, `NM_001039469.3:c.1181dup`, `NM_001039469.3:c.1181dupA`, `NM_001163296.2:c.1181dup`, `NM_001163297.2:c.1181dup`, `NM_004954.5:c.1181dup`, `NM_017490.4:c.1082dup`

## 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 0.432, GERP -0.205, phastCons 0.994 — weakly conserved 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 12 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 duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **395** lies in a UniProt-annotated variant site (in mrd76; likely pathogenic); a UniProt-annotated variant site (in mrd76; pathogenic); the 'disordered' region.

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.Val395fs falls in the disordered region.


### 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-07-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Medical Genetics, Capital Institute of Pediatrics | Pathogenic | no assertion criteria provided | research | 2024-07-03 |

## Associated conditions {#conditions}

[autism spectrum disorder](https://sugi.bio/atlas/disease/autism-spectrum-disorder/).

**Reported phenotype names (ClinVar):** Autism spectrum disorder, Autism spectrum disorders.

## Similar variants {#similar}

Related MARK2 variant pages (same residue, condition, or type): [MARK2 p.Ala630fs](/variant/mark2-p-ala630fs), [MARK2 p.Val395Ala](/variant/mark2-p-val395ala), [MARK2 p.Leu506fs](/variant/mark2-p-leu506fs), [MARK2 p.Leu97fs](/variant/mark2-p-leu97fs), [MARK2 p.Thr87fs](/variant/mark2-p-thr87fs), [MARK2 c.1934+1G>A](/variant/mark2-c-1934-plus-1g-a), [MARK2 c.337+1G>T](/variant/mark2-c-337-plus-1g-t), [MARK2 p.Arg584Ter](/variant/mark2-p-arg584ter).

### 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 3253629). 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.*