Is MET p.Pro1364Ser (c.4090C>T) pathogenic?

MET p.Pro1364Ser (c.4090C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.3124); Very rare (popmax 0.00246%, nfe); Associated with renal cell carcinoma.

What condition is associated with MET p.Pro1364Ser (c.4090C>T)?

MET p.Pro1364Ser (c.4090C>T) is associated with renal cell carcinoma, hepatocellular carcinoma, osteofibrous dysplasia (ClinVar).

How common is MET p.Pro1364Ser (c.4090C>T) in the general population?

MET p.Pro1364Ser (c.4090C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about MET p.Pro1364Ser (c.4090C>T)?

AlphaMissense predicts likely benign (score 0.3124) — an in-silico prediction, not a clinical call.

MET p.Pro1364Ser

c.4090C>T · rs765332671 · VCV485750

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.3124	likely benign
REVEL	0.527	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	24.9	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 0.00246% European (non-Finnish) · 29/1,179,926 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,613,854 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,687
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro1364Ser
Coding: c.4090C>T
MANE Select: NM_000245
dbSNP: rs765332671
Type: single nucleotide variant
Location: chr7:116796041 (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: hepatocellular carcinoma osteofibrous dysplasia autosomal recessive nonsyndromic hearing loss 97 hereditary neoplastic syndrome

Similar variants

MET p.Pro1364= Benign ★★ same residue
MET p.Pro1364Leu 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-pro1364ser (accessed [today's date]).

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