# NM_001039469.3(MARK2):c.1667C>T (p.Pro556Leu)

https://sugi.bio/variant/mark2-p-pro556leu

## Summary

**MARK2 p.Pro556Leu (c.1667C>T)** is classified **Uncertain significance** in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.00459%, eas); Associated with intellectual developmental disorder, autosomal dominant 76.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00459%, eas)

## 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 1 submitter, and is linked to intellectual developmental disorder, autosomal dominant 76.

*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 | [MARK2](https://sugi.bio/atlas/gene/MARK2/) |
| Protein change (HGVS p.) | p.Pro556Leu |
| Coding change (HGVS c.) | c.1667C>T |
| MANE Select transcript | [NM_001039469](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039469) |
| Variant type | single nucleotide variant |
| Location | chr11:63904138-63904138 (GRCh38) |
| ClinVar | [VCV4882601](https://www.ncbi.nlm.nih.gov/clinvar/variation/4882601/) |

**All HGVS expressions:** `NC_000011.10:g.63904138C>T`, `NC_000011.9:g.63671610C>T`, `NG_029771.1:g.70211C>T`, `NM_001039469.3:c.1667C>T`, `NM_001163296.2:c.1515-648C>T`, `NM_001163297.2:c.1512-648C>T`, `NM_004954.5:c.1512-648C>T`, `NM_017490.4:c.1565C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0762)
- REVEL 0.087 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.527 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.842, GERP 0.583, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.0**. 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 0.70** across the covering region of the MANE Select transcript (63,900,662–63,908,979), spanning 8,317 bp. Chi-square p 7.7e-13. 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>G, Δ0.71 donor 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 **0.00459%** (eas) · FAF95 0.000762% · FAF99 0.000316% · 2/43,530 in the highest group · 31/1,579,636 alleles overall — very rare (popmax 0.00459%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0345% | 2,900 |
| East Asian (grpmax) | 0.00459% | 21,765 |
| South Asian | 0.00113% | 88,356 |
| European (non-Finnish) | 0.000856% | 116,844 |

Finnish 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}

**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 **556** 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.Pro556Leu 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-02 |

## Associated conditions {#conditions}

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

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

## 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 c.1101+5G>A](/variant/mark2-c-1101-plus-5g-a), [MARK2 p.Arg302Ter](/variant/mark2-p-arg302ter), [MARK2 p.Arg71Ter](/variant/mark2-p-arg71ter), [MARK2 p.Asp410Glu](/variant/mark2-p-asp410glu).

### 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 4882601). 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.*