Is MET p.Val658Ala (c.1973T>C) pathogenic?

MET p.Val658Ala (c.1973T>C) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-11-21). AlphaMissense: likely benign (0.1137); Absent from gnomAD v4.1; Associated with renal cell carcinoma.

What condition is associated with MET p.Val658Ala (c.1973T>C)?

MET p.Val658Ala (c.1973T>C) is associated with renal cell carcinoma (ClinVar).

How common is MET p.Val658Ala (c.1973T>C) in the general population?

MET p.Val658Ala (c.1973T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MET p.Val658Ala (c.1973T>C)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

MET p.Val658Ala

c.1973T>C · rs1584941533 · VCV661068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.35, phastCons 0.99
Overall
CADD	16.08	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MET
Protein: p.Val658Ala
Coding: c.1973T>C
MANE Select: NM_000245
dbSNP: rs1584941533
Type: single nucleotide variant
Location: chr7:116757645 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 658: a β-strand; the ipt/tig 2 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.Val658= Likely benign ★★ same residue
MET p.Val658Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Val658Leu Conflicting classifications of pathogenicity ★ ⚠ 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
MET c.1200+2T>C Uncertain significance ★★ 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-val658ala (accessed [today's date]).

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