Is MET p.Ile377Val (c.1129A>G) pathogenic?

MET p.Ile377Val (c.1129A>G) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-05). AlphaMissense: likely benign (0.1378); Very rare (popmax 8.52e-05%, nfe); Associated with renal cell carcinoma.

What condition is associated with MET p.Ile377Val (c.1129A>G)?

MET p.Ile377Val (c.1129A>G) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ile377Val (c.1129A>G) in the general population?

MET p.Ile377Val (c.1129A>G) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about MET p.Ile377Val (c.1129A>G)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

MET p.Ile377Val

c.1129A>G · rs1554379158 · VCV485758

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -4.95	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 11	GERP 1.9, phastCons 1
Overall
CADD	19.19	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

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,174,238 alleles

Overall 6.93e-05% 1/1,442,762 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.Ile377Val
Coding: c.1129A>G
MANE Select: NM_000245
dbSNP: rs1554379158
Type: single nucleotide variant
Location: chr7:116700213 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 377: 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

Also linked: hereditary neoplastic syndrome

Similar variants

MET p.Ile377Ser Uncertain significance ★★ ⚠ same residue
MET p.Ile377= Likely benign ★★ same residue
MET p.Ile377Met Uncertain significance ★ ⚠ same residue
MET p.Ile377Thr 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
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-ile377val (accessed [today's date]).

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