# NM_006343.3(MERTK):c.60A>T (p.Arg20Ser)

https://sugi.bio/variant/mertk-p-arg20ser

## Summary

**MERTK p.Arg20Ser (c.60A>T)** is classified **Conflicting classifications of pathogenicity** in MERTK (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1178); Common (popmax 7.52%, mid) — too common for a highly-penetrant pathogenic allele; Associated with retinitis pigmentosa.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs35898499 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · common (popmax 7.52%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the MERTK gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to retinitis pigmentosa.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MERTK is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/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.Arg20Ser |
| Coding change (HGVS c.) | c.60A>T |
| MANE Select transcript | [NM_006343](https://www.ncbi.nlm.nih.gov/nuccore/NM_006343) |
| dbSNP | [rs35898499](https://www.ncbi.nlm.nih.gov/snp/rs35898499/) |
| Variant type | single nucleotide variant |
| Location | chr2:111898795-111898795 (GRCh38) |
| ClinVar | [VCV95372](https://www.ncbi.nlm.nih.gov/clinvar/variation/95372/) |

**All HGVS expressions:** `NC_000002.11:g.112656372A>T`, `NC_000002.12:g.111898795A>T`, `NG_011607.1:g.5182A>T`, `NM_006343.3:c.60A>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.52%, mid) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1178)
- REVEL 0.076 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.352 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.96, GERP -2, phastCons 0.984 — weakly conserved position
- CADD: **PHRED 14.73**. 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 0.90** across the covering region of the MANE Select transcript (111,898,736–112,028,861), spanning 130,125 bp. Chi-square p 0.00043. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **7.52%** (mid) · FAF95 6.94% · FAF99 6.72% · 448/5,958 in the highest group · 64,669/1,591,892 alleles overall — common (popmax 7.52%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 12.2% | 8 |
| Middle Eastern (grpmax) | 7.52% | 13 |
| Amish (not grpmax-eligible) | 5.59% | 18 |
| Remaining individuals (not grpmax-eligible) | 4.52% | 22 |
| European (non-Finnish) | 4.5% | 22 |
| Finnish (not grpmax-eligible) | 2.88% | 35 |
| Admixed American | 2.65% | 38 |
| South Asian | 1.47% | 68 |
| African / African-American | 0.773% | 129 |
| East Asian | 0.0137% | 7,311 |

Ashkenazi Jewish 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}

**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 **20** lies in a UniProt-annotated variant site (in).

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:** MERTK participates in disease-associated pathways. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (2 Benign, 2 Likely benign, 1 not provided, 1 Uncertain significance).

**Submission history:** 44 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| NEI Ophthalmic Genomics Laboratory, National Institutes of Health | not provided | no classification provided | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2013-08-20 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| DBGen Ocular Genomics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-01-01 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/), [retinitis pigmentosa 38](https://sugi.bio/atlas/disease/retinitis-pigmentosa-38/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa, not specified, not provided, Retinitis pigmentosa 38, Uterine carcinosarcoma, Thymoma, Familial pancreatic carcinoma, Lymphoma, Thyroid cancer, nonmedullary, 1, Acute myeloid leukemia.

## Similar variants {#similar}

Related MERTK variant pages (same residue, condition, or type): [MERTK p.Arg20Thr](/variant/mertk-p-arg20thr), [MERTK c.1296+1G>A](/variant/mertk-c-1296-plus-1g-a), [MERTK c.1605-2A>G](/variant/mertk-c-1605-minus-2a-g), [MERTK c.1867+1G>A](/variant/mertk-c-1867-plus-1g-a), [MERTK c.1868-1G>A](/variant/mertk-c-1868-minus-1g-a), [MERTK c.2189+1G>T](/variant/mertk-c-2189-plus-1g-t), [MERTK p.Ala768Thr](/variant/mertk-p-ala768thr), [MERTK p.Ala768Val](/variant/mertk-p-ala768val).

### 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 95372). 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.*