Is MET p.Pro351Ala (c.1051C>G) pathogenic?

MET p.Pro351Ala (c.1051C>G) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.066); Very rare (popmax 0.000597%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Pro351Ala (c.1051C>G)?

MET p.Pro351Ala (c.1051C>G) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Pro351Ala (c.1051C>G) in the general population?

MET p.Pro351Ala (c.1051C>G) is very rare (popmax 0.000597%, nfe) (gnomAD).

What do computational predictors say about MET p.Pro351Ala (c.1051C>G)?

AlphaMissense predicts likely benign (score 0.066) — an in-silico prediction, not a clinical call.

MET p.Pro351Ala

c.1051C>G · rs587782807 · VCV142899

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000597%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.066	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.46	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 4.8	GERP 1.9, phastCons 1
Overall
CADD	23.3	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 0.000597% European (non-Finnish) · 7/1,173,266 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000484% 7/1,446,996 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.Pro351Ala
Coding: c.1051C>G
MANE Select: NM_000245
dbSNP: rs587782807
Type: single nucleotide variant
Location: chr7:116700135 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 351: a disulfide bond; the sema domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma

Similar variants

MET p.Pro351Leu Uncertain significance ★★ ⚠ same residue
MET p.Pro351Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Pro351Thr 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
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-pro351ala (accessed [today's date]).

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