Is MET p.Arg280Ser (c.840G>C) pathogenic?

MET p.Arg280Ser (c.840G>C) is classified Uncertain significance in MET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9663); Very rare (popmax 0.0011%, sas); Associated with renal cell carcinoma.

What condition is associated with MET p.Arg280Ser (c.840G>C)?

MET p.Arg280Ser (c.840G>C) is associated with renal cell carcinoma (ClinVar).

How common is MET p.Arg280Ser (c.840G>C) in the general population?

MET p.Arg280Ser (c.840G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MET p.Arg280Ser (c.840G>C)?

AlphaMissense predicts likely pathogenic (score 0.9663) — an in-silico prediction, not a clinical call.

MET p.Arg280Ser

c.840G>C · VCV4741061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.9663	likely pathogenic · top 10% in MET
REVEL	0.528	indeterminate
SaProt	LLR -13.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.26, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 6.84e-05% 1/1,461,798 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MET
Protein: p.Arg280Ser
Coding: c.840G>C
MANE Select: NM_000245
Type: single nucleotide variant
Location: chr7:116699924 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 280: a β-strand; the sema domain

Full MET gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

renal cell carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MET p.Arg280Gly Uncertain significance ★★ ⚠ same residue
MET p.Arg280Lys Uncertain significance ★★ ⚠ same residue
MET p.Arg280Thr Uncertain significance ★★ ⚠ same residue
MET p.Arg280= Likely benign ★★ same residue
MET p.Arg280Met Uncertain significance ★ ⚠ same residue
MET p.His1094Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
MET p.Met1131Thr Pathogenic/Likely pathogenic ★★ same condition
MET p.Val1092Ile Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/met-p-arg280ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown