Is MET p.Pro366Ala (c.1096C>G) pathogenic?

MET p.Pro366Ala (c.1096C>G) is classified Uncertain significance in MET (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-03). AlphaMissense: ambiguous (0.4541); Very rare (popmax 0.00116%, sas); Associated with renal cell carcinoma.

What condition is associated with MET p.Pro366Ala (c.1096C>G)?

MET p.Pro366Ala (c.1096C>G) is associated with renal cell carcinoma (ClinVar).

How common is MET p.Pro366Ala (c.1096C>G) in the general population?

MET p.Pro366Ala (c.1096C>G) is very rare (popmax 0.00116%, sas) (gnomAD).

What do computational predictors say about MET p.Pro366Ala (c.1096C>G)?

AlphaMissense predicts ambiguous (score 0.4541) — an in-silico prediction, not a clinical call.

MET p.Pro366Ala

c.1096C>G · rs2116605388 · VCV2842364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.4541	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -8.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	20.4	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 0.00116% South Asian · 1/86,382 alleles

Overall 6.28e-05% 1/1,593,514 alleles · very rare exomes 1/1,441,240 · genomes 0/152,274 · joint denominator

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.Pro366Ala
Coding: c.1096C>G
MANE Select: NM_000245
dbSNP: rs2116605388
Type: single nucleotide variant
Location: chr7:116700180 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 366: 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.Pro366Ser Uncertain significance ★ ⚠ same residue
MET p.Pro366Thr 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
MET c.1200+2T>C Uncertain significance ★★ same condition
MET c.1392+1G>T 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-pro366ala (accessed [today's date]).

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