Is MET p.Pro1364Leu (c.4091C>T) pathogenic?

MET p.Pro1364Leu (c.4091C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-22). AlphaMissense: ambiguous (0.4273); Ultra-rare (popmax 0.0494%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Pro1364Leu (c.4091C>T)?

MET p.Pro1364Leu (c.4091C>T) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Pro1364Leu (c.4091C>T) in the general population?

MET p.Pro1364Leu (c.4091C>T) is ultra-rare (popmax 0.0494%, afr) (gnomAD).

What do computational predictors say about MET p.Pro1364Leu (c.4091C>T)?

AlphaMissense predicts ambiguous (score 0.4273) — an in-silico prediction, not a clinical call.

MET p.Pro1364Leu

c.4091C>T · rs752791731 · VCV246645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4273 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4273	ambiguous
REVEL	0.639	indeterminate
SaProt	LLR -7.78	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Overall
CADD	27.2	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

Grpmax group 0.0494% African / African-American · 37/74,884 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00428% 69/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0494%	2,024
South Asian	0.0121%	8,279
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.00153%	65,551

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.Pro1364Leu
Coding: c.4091C>T
MANE Select: NM_000245
dbSNP: rs752791731
Type: single nucleotide variant
Location: chr7:116796042 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 1364: the 'interaction with ranbp9' region

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.Pro1364= Benign ★★ same residue
MET p.Pro1364Ser 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
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-pro1364leu (accessed [today's date]).

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