# NM_006343.3(MERTK):c.444dup (p.Pro149fs)

https://sugi.bio/variant/mertk-p-pro149fs

## Summary

**MERTK p.Pro149fs (c.444dup)** is classified **Pathogenic** in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). Very rare (popmax 0.0011%, sas); Associated with inherited retinal dystrophy.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the MERTK gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to inherited retinal dystrophy.

*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 | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MERTK](https://sugi.bio/atlas/gene/MERTK/) |
| Protein change (HGVS p.) | p.Pro149fs |
| Coding change (HGVS c.) | c.444dup |
| MANE Select transcript | [NM_006343](https://www.ncbi.nlm.nih.gov/nuccore/NM_006343) |
| Variant type | Duplication |
| Location | chr2:111929501-111929502 (GRCh38) |
| ClinVar | [VCV3381808](https://www.ncbi.nlm.nih.gov/clinvar/variation/3381808/) |

**All HGVS expressions:** `NC_000002.11:g.112687079dup`, `NC_000002.12:g.111929502dup`, `NG_011607.1:g.35889dup`, `NM_006343.3:c.444dup`

## Computational & population evidence {#evidence}

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

- **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 7.936, GERP 6.9, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.787, pLI 1.6072e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 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 (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,038 in the highest group · 1/1,461,688 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**MERTK** population constraint: LOEUF 0.787, pLI 1.6072e-12, missense-Z 1.7698. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **MERTK-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **149** lies in a disulfide bond; the ig-like c2-type 1 domain.

AlphaFold model confidence (whole protein): pLDDT 72.78, 38% of residues very-high.

**42 experimental structure(s)** (PDB): [2DBJ](https://www.rcsb.org/structure/2DBJ), [2P0C](https://www.rcsb.org/structure/2P0C), [3BPR](https://www.rcsb.org/structure/3BPR), [3BRB](https://www.rcsb.org/structure/3BRB), [3TCP](https://www.rcsb.org/structure/3TCP), [4M3Q](https://www.rcsb.org/structure/4M3Q) — incl. mutant structure 5TC0.

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

*Describes the biological roles of MERTK (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:** p.Pro149fs falls in the ig-like c2-type 1 domain. In Reactome, MERTK is annotated in disease pathway(s) including **Dengue Virus Attachment and Entry**.

**Disease mechanism (Reactome):** MERTK loss or alteration is curated in [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485).

### Pathways affected {#pathways}

MERTK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |

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

**Biological process:** phagocytosis, positive regulation of phagocytosis, negative regulation of leukocyte apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Pathogenic | criteria provided, single submitter | research | 2024-05-27 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, Inherited retinal dystrophy.

## Similar variants {#similar}

Related MERTK variant pages (same residue, condition, or type): [MERTK c.2189+1G>T](/variant/mertk-c-2189-plus-1g-t), [MERTK p.Ala768Thr](/variant/mertk-p-ala768thr), [MERTK p.Arg651Ter](/variant/mertk-p-arg651ter), [MERTK p.Arg722Ter](/variant/mertk-p-arg722ter), [MERTK p.Arg727Ter](/variant/mertk-p-arg727ter), [MERTK p.Arg732Ter](/variant/mertk-p-arg732ter), [MERTK p.Arg775Ter](/variant/mertk-p-arg775ter), [MERTK p.Arg844Cys](/variant/mertk-p-arg844cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3381808). 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.*