# NM_000245.4(MET):c.629del (p.Pro210fs)

https://sugi.bio/variant/met-p-pro210fs

## Summary

**MET p.Pro210fs (c.629del)** is classified **Uncertain significance** in MET (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-19). No gnomAD frequency available for this variant; Associated with renal cell carcinoma.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1554378645 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MET gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to renal cell carcinoma.

*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 | 993 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013215/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MET](https://sugi.bio/atlas/gene/MET/) |
| Protein change (HGVS p.) | p.Pro210fs |
| Coding change (HGVS c.) | c.629del |
| MANE Select transcript | [NM_000245](https://www.ncbi.nlm.nih.gov/nuccore/NM_000245) |
| dbSNP | [rs1554378645](https://www.ncbi.nlm.nih.gov/snp/rs1554378645/) |
| Variant type | Deletion |
| Location | chr7:116699712-116699712 (GRCh38) |
| ClinVar | [VCV454254](https://www.ncbi.nlm.nih.gov/clinvar/variation/454254/) |

**All HGVS expressions:** `LRG_662:g.32309del`, `LRG_662t1:c.629del`, `NC_000007.13:g.116339767del`, `NC_000007.14:g.116699713del`, `NG_008996.1:g.32309del`, `NM_000245.4:c.629del`, `NM_001127500.3:c.629del`, `NM_001324401.3:c.629del`, `NM_001324402.2:c.-91+27136del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.274, GERP -1.86, phastCons 0.801 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.446, pLI 0.99985), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 21**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**MET** population constraint: LOEUF 0.446, pLI 0.99985, missense-Z 2.9693. *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):

- **papillary renal cell carcinoma** — Definitive (AD)
- **complex neurodevelopmental disorder** — Disputed (AD)
- **nonsyndromic genetic hearing loss** — Limited (AR)

## Protein context {#protein}

Residue **210** lies in the sema domain.

AlphaFold model confidence (whole protein): pLDDT 79.28, 43% of residues very-high.

**130 experimental structure(s)** (PDB): [11HQ](https://www.rcsb.org/structure/11HQ), [1FYR](https://www.rcsb.org/structure/1FYR), [1R0P](https://www.rcsb.org/structure/1R0P), [1R1W](https://www.rcsb.org/structure/1R1W), [1SHY](https://www.rcsb.org/structure/1SHY), [1SSL](https://www.rcsb.org/structure/1SSL) — incl. mutant structure 3DKG.

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

*Describes the biological roles of MET (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:** MET's established molecular role includes protein phosphatase binding. p.Pro210fs falls in the sema domain. In Reactome, MET is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **InlB-mediated entry of Listeria monocytogenes into host cell**.

**Disease mechanism (Reactome):** MET loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [InlB-mediated entry of Listeria monocytogenes into host cell](https://reactome.org/content/detail/R-HSA-8875360).

### Pathways affected {#pathways}

MET participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [InlB-mediated entry of Listeria monocytogenes into host cell](https://reactome.org/content/detail/R-HSA-8875360) | electronic |
| [Drug-mediated inhibition of MET activation](https://reactome.org/content/detail/R-HSA-9734091) | curated |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | curated |
| [MET Receptor Activation](https://reactome.org/content/detail/R-HSA-6806942) | curated |
| [MET activates PI3K/AKT signaling](https://reactome.org/content/detail/R-HSA-8851907) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [MET activates PTPN11](https://reactome.org/content/detail/R-HSA-8865999) | curated |
| [MET activates RAP1 and RAC1](https://reactome.org/content/detail/R-HSA-8875555) | curated |
| [MET activates RAS signaling](https://reactome.org/content/detail/R-HSA-8851805) | curated |
| [MET activates STAT3](https://reactome.org/content/detail/R-HSA-8875791) | curated |
| [MET interacts with TNS proteins](https://reactome.org/content/detail/R-HSA-8875513) | curated |
| [MET receptor recycling](https://reactome.org/content/detail/R-HSA-8875656) | curated |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | curated |
| [Sema4D mediated inhibition of cell attachment and migration](https://reactome.org/content/detail/R-HSA-416550) | curated |

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

**Molecular function:** protein phosphatase binding, identical protein binding, molecular function activator activity.

**Biological process:** endothelial cell morphogenesis, positive regulation of transcription by RNA polymerase II, hepatocyte growth factor receptor signaling pathway, branching morphogenesis of an epithelial tube, positive chemotaxis, semaphorin-plexin signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-05-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-19 |

## Associated conditions {#conditions}

[renal cell carcinoma](https://sugi.bio/atlas/disease/renal-cell-carcinoma/).

**Reported phenotype names (ClinVar):** Renal cell carcinoma.

## Similar variants {#similar}

Related MET variant pages (same residue, condition, or type): [MET p.Pro210=](/variant/met-p-pro210), [MET p.Pro210Ser](/variant/met-p-pro210ser), [MET p.Pro210Thr](/variant/met-p-pro210thr), [MET p.Gly1119del](/variant/met-p-gly1119del), [MET p.His1052fs](/variant/met-p-his1052fs), [MET p.Leu893fs](/variant/met-p-leu893fs), [MET p.Met1fs](/variant/met-p-met1fs), [MET p.Phe258fs](/variant/met-p-phe258fs).

### 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 454254). 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.*