# NM_001128918.3(MARK3):c.1661G>A (p.Arg554His)

https://sugi.bio/variant/mark3-p-arg554his

## Summary

**MARK3 p.Arg554His (c.1661G>A)** is classified **Uncertain significance** in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs369866994 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the MARK3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [MARK3](https://sugi.bio/atlas/gene/MARK3/) |
| Protein change (HGVS p.) | p.Arg554His |
| Coding change (HGVS c.) | c.1661G>A |
| MANE Select transcript | [NM_001128918](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128918) |
| dbSNP | [rs369866994](https://www.ncbi.nlm.nih.gov/snp/rs369866994/) |
| Variant type | single nucleotide variant |
| Location | chr14:103491851-103491851 (GRCh38) |
| ClinVar | [VCV2407188](https://www.ncbi.nlm.nih.gov/clinvar/variation/2407188/) |

**All HGVS expressions:** `NC_000014.8:g.103958188G>A`, `NC_000014.9:g.103491851G>A`, `NG_030339.2:g.111488G>A`, `NM_001128918.3:c.1661G>A`, `NM_001128919.3:c.1661G>A`, `NM_001128920.3:c.1613G>A`, `NM_001128921.3:c.1424G>A`, `NM_001411055.1:c.1607G>A`, `NM_001411056.1:c.1469G>A`, `NM_002376.7:c.1661G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0804)
- REVEL 0.167 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.035 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.623, GERP 0.805, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.91** across the covering region of the MANE Select transcript (103,466,011–103,503,224), spanning 37,213 bp. Chi-square p 0.031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MARK3 (1,282 scored positions, the nearest 9 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00402% · FAF99 0.00362% · 1/6,084 in the highest group · 68/1,613,980 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| European (non-Finnish) | 0.00508% | 19,667 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| African / African-American | 0.00267% | 37,452 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,006 |
| South Asian | 0.0011% | 91,090 |

*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}

**MARK3** population constraint: LOEUF 0.73, pLI 9.5191e-05, missense-Z 1.6367. *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 **554** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.25, 43% of residues very-high.

**14 experimental structure(s)** (PDB): [2QNJ](https://www.rcsb.org/structure/2QNJ), [3FE3](https://www.rcsb.org/structure/3FE3), [7P1L](https://www.rcsb.org/structure/7P1L), [8UOH](https://www.rcsb.org/structure/8UOH), [8UOI](https://www.rcsb.org/structure/8UOI), [8UOJ](https://www.rcsb.org/structure/8UOJ) — incl. mutant structure 3FE3.

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

*Describes the biological roles of MARK3 (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:** MARK3's established molecular role includes protein serine/threonine kinase activity. p.Arg554His falls in the disordered region. In Reactome, MARK3 is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** MARK3 loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223).

### Pathways affected {#pathways}

MARK3 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |

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

**Molecular function:** protein serine/threonine kinase activity, protein phosphatase binding, tau-protein kinase activity.

**Biological process:** protein phosphorylation, regulation of G2/M transition of mitotic cell cycle, negative regulation of hippo signaling, negative regulation of protein localization to nucleus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related MARK3 variant pages (same residue, condition, or type): [MARK3 c.413-4A>G](/variant/mark3-c-413-minus-4a-g), [MARK3 c.1917-11A>G](/variant/mark3-c-1917-minus-11a-g), [MARK3 p.Ala373Ser](/variant/mark3-p-ala373ser), [MARK3 p.Ala481Gly](/variant/mark3-p-ala481gly), [MARK3 p.Ala739Val](/variant/mark3-p-ala739val), [MARK3 p.Ala748Asp](/variant/mark3-p-ala748asp), [MARK3 p.Arg262Lys](/variant/mark3-p-arg262lys), [MARK3 p.Arg305Lys](/variant/mark3-p-arg305lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2407188). 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.*