# NM_000245.4(MET):c.9C>T (p.Ala3=)

https://sugi.bio/variant/met-p-ala3

## Summary

**MET p.Ala3= (c.9C>T)** is classified **Likely benign** in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-08). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1797064273 · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MET gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary neoplastic syndrome.

*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 | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Ala3= |
| Coding change (HGVS c.) | c.9C>T |
| MANE Select transcript | [NM_000245](https://www.ncbi.nlm.nih.gov/nuccore/NM_000245) |
| dbSNP | [rs1797064273](https://www.ncbi.nlm.nih.gov/snp/rs1797064273/) |
| Variant type | single nucleotide variant |
| Location | chr7:116699093-116699093 (GRCh38) |
| ClinVar | [VCV1154382](https://www.ncbi.nlm.nih.gov/clinvar/variation/1154382/) |

**All HGVS expressions:** `LRG_662:g.31689C>T`, `LRG_662t1:c.9C>T`, `NC_000007.13:g.116339147C>T`, `NC_000007.14:g.116699093C>T`, `NG_008996.1:g.31689C>T`, `NM_000245.4:c.9C>T`, `NM_001127500.3:c.9C>T`, `NM_001324401.3:c.9C>T`, `NM_001324402.2:c.-91+26516C>T`

## 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 -0.43, GERP -0.12 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.42**. 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: **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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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. 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-09-08.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-03-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Renal cell carcinoma, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related MET variant pages (same residue, condition, or type): [MET p.Ala3Asp](/variant/met-p-ala3asp), [MET p.Ala3Thr](/variant/met-p-ala3thr), [MET p.Ala3Val](/variant/met-p-ala3val), [MET p.His1094Arg](/variant/met-p-his1094arg), [MET p.Met1131Thr](/variant/met-p-met1131thr), [MET p.Val1092Ile](/variant/met-p-val1092ile), [MET p.Val1220Ile](/variant/met-p-val1220ile), [MET c.1200+2T>C](/variant/met-c-1200-plus-2t-c).

### 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 1154382). 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.*