# NM_006343.3(MERTK):c.1191T>C (p.Ser397=)

https://sugi.bio/variant/mertk-p-ser397

## Summary

**MERTK p.Ser397= (c.1191T>C)** is classified **Likely benign** in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-08). Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs2104741150 · 1 submitter · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the MERTK gene that is classified as likely benign — not considered disease-causing, 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 | [MERTK](https://sugi.bio/atlas/gene/MERTK/) |
| Protein change (HGVS p.) | p.Ser397= |
| Coding change (HGVS c.) | c.1191T>C |
| MANE Select transcript | [NM_006343](https://www.ncbi.nlm.nih.gov/nuccore/NM_006343) |
| dbSNP | [rs2104741150](https://www.ncbi.nlm.nih.gov/snp/rs2104741150/) |
| Variant type | single nucleotide variant |
| Location | chr2:111982888-111982888 (GRCh38) |
| ClinVar | [VCV1154193](https://www.ncbi.nlm.nih.gov/clinvar/variation/1154193/) |

**All HGVS expressions:** `NC_000002.11:g.112740465T>C`, `NC_000002.12:g.111982888T>C`, `NG_011607.1:g.89275T>C`, `NM_006343.3:c.1191T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.511, GERP -2.78 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.101**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 3 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,956 in the highest group · 1/1,461,800 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **397** lies in a β-strand; the fibronectin type-iii 2 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.Ser397= falls in the fibronectin type-iii 2 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-08-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-08-08 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MERTK variant pages (same residue, condition, or type): [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.1787-2A>T](/variant/mertk-c-1787-minus-2a-t), [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 2026-10-11); 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 1154193). 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.*