Is MET p.Pro1364= (c.4092G>A) pathogenic?

MET p.Pro1364= (c.4092G>A) is classified Benign in MET (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Common (popmax 49.4%, amr) — too common for a highly-penetrant pathogenic allele; Associated with renal cell carcinoma.

What condition is associated with MET p.Pro1364= (c.4092G>A)?

MET p.Pro1364= (c.4092G>A) is associated with renal cell carcinoma, autosomal recessive nonsyndromic hearing loss 97, hereditary neoplastic syndrome (ClinVar).

MET p.Pro1364=

Q: How common is MET p.Pro1364= (c.4092G>A) in the general population?

MET p.Pro1364= (c.4092G>A) is common (popmax 49.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4092G>A · rs41737 · VCV93576

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 49.4%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

renal cell carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.9	GERP -3.6
Overall
CADD	0.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 49.4% Admixed American · 29,645/59,998 alleles

Filtering AF 48.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 48.7%

Overall 43.6% 703,003/1,613,794 alleles · common exomes 649,708/1,461,784 · genomes 53,295/152,010 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	49.4%	2
Ashkenazi Jewishnot grpmax-eligible	49%	2
East Asian	48.7%	2
South Asian	45.5%	2
European (non-Finnish)	45.1%	2
Remaining individualsnot grpmax-eligible	44%	2
Middle Eastern	42.7%	2
Finnishnot grpmax-eligible	39.7%	3
Amishnot grpmax-eligible	30.5%	3
African / African-American	9.68%	10

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.Pro1364=
Coding: c.4092G>A
MANE Select: NM_000245
dbSNP: rs41737
Type: single nucleotide variant
Location: chr7:116796043 (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

renal cell carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 97 hereditary neoplastic syndrome

Similar variants

MET p.Pro1364Leu Conflicting classifications of pathogenicity ★ 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-pro1364 (accessed [today's date]).

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