Is MET p.Arg461Ser (c.1381C>A) pathogenic?

MET p.Arg461Ser (c.1381C>A) is classified Uncertain significance in MET (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: ambiguous (0.5402); No allele count reported in gnomAD v4.1 (AN 1,613,938); Associated with renal cell carcinoma.

What condition is associated with MET p.Arg461Ser (c.1381C>A)?

MET p.Arg461Ser (c.1381C>A) is associated with renal cell carcinoma (ClinVar).

How common is MET p.Arg461Ser (c.1381C>A) in the general population?

MET p.Arg461Ser (c.1381C>A) is no allele count reported in gnomAD v4.1 (AN 1,613,938) (gnomAD).

What do computational predictors say about MET p.Arg461Ser (c.1381C>A)?

AlphaMissense predicts ambiguous (score 0.5402) — an in-silico prediction, not a clinical call.

MET p.Arg461Ser

c.1381C>A · rs1584914359 · VCV2854357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5402 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,938)

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.5402	ambiguous
REVEL	0.502	indeterminate
SaProt	LLR -8.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,938). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MET
Protein: p.Arg461Ser
Coding: c.1381C>A
MANE Select: NM_000245
dbSNP: rs1584914359
Type: single nucleotide variant
Location: chr7:116731848 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 461: 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.Arg461Cys Uncertain significance ★★ ⚠ same residue
MET p.Arg461Gly Uncertain significance ★★ same residue
MET p.Arg461His Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Arg461= Likely benign ★ 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
MET p.Val1220Ile 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-arg461ser (accessed [today's date]).

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