# NM_001039469.3(MARK2):c.239C>T (p.Ala80Val)

https://sugi.bio/variant/mark2-p-ala80val

## Summary

**MARK2 p.Ala80Val (c.239C>T)** is classified **Pathogenic/Likely pathogenic** in MARK2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2025-07-25). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with autism spectrum disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs2539306253 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MARK2 gene that is considered likely disease-causing, submitted by 2 submitters, 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.Ala80Val |
| Coding change (HGVS c.) | c.239C>T |
| MANE Select transcript | [NM_001039469](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039469) |
| dbSNP | [rs2539306253](https://www.ncbi.nlm.nih.gov/snp/rs2539306253/) |
| Variant type | single nucleotide variant |
| Location | chr11:63895584-63895584 (GRCh38) |
| ClinVar | [VCV3253643](https://www.ncbi.nlm.nih.gov/clinvar/variation/3253643/) |

**All HGVS expressions:** `NC_000011.10:g.63895584C>T`, `NC_000011.9:g.63663056C>T`, `NG_029771.1:g.61657C>T`, `NM_001039469.3:c.239C>T`, `NM_001163296.2:c.239C>T`, `NM_001163297.2:c.239C>T`, `NM_004954.5:c.239C>T`, `NM_017490.4:c.140C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9987) — concordant with the pathogenic call
- REVEL 0.624 (indeterminate)
- SaProt LLR -14.978 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.661, GERP 1.91, 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 0.29** across the covering region of the MANE Select transcript (63,895,268–63,900,661), spanning 5,393 bp — the region is depleted of missense variation. Chi-square p 7.7e-34. 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 (C>A, Δ0.28 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

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

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.Ala80Val 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}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2025-07-25.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Medical Genetics, Capital Institute of Pediatrics | Likely pathogenic | no assertion criteria provided | research | 2024-07-03 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2025-07-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Autism spectrum disorder, Intellectual developmental disorder, autosomal dominant 76, Autism spectrum disorders.

## Similar variants {#similar}

Related MARK2 variant pages (same residue, condition, or type): [MARK2 p.Ala432Thr](/variant/mark2-p-ala432thr), [MARK2 c.1934+1G>A](/variant/mark2-c-1934-plus-1g-a), [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.Arg584Ter](/variant/mark2-p-arg584ter), [MARK2 p.Gly135Arg](/variant/mark2-p-gly135arg), [MARK2 c.1101+5G>A](/variant/mark2-c-1101-plus-5g-a), [MARK2 p.Arg302Ter](/variant/mark2-p-arg302ter).

### 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 3253643). 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.*