Is MET p.Ile565Val (c.1693A>G) pathogenic?

MET p.Ile565Val (c.1693A>G) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-29). AlphaMissense: likely benign (0.0656); Very rare (popmax 0.00879%, sas); Associated with Papillary renal cell carcinoma type 1.

What condition is associated with MET p.Ile565Val (c.1693A>G)?

MET p.Ile565Val (c.1693A>G) is associated with Papillary renal cell carcinoma type 1, renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ile565Val (c.1693A>G) in the general population?

MET p.Ile565Val (c.1693A>G) is very rare (popmax 0.00879%, sas) (gnomAD).

What do computational predictors say about MET p.Ile565Val (c.1693A>G)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

MET p.Ile565Val

c.1693A>G · rs745479104 · VCV358686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Papillary renal cell carcinoma type 1

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.56	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 -0.41	GERP -3.8
Overall
CADD	0.236	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 0.00879% South Asian · 8/90,974 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000889% 13/1,461,756 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,372
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00134%	74,648
European (non-Finnish)	0.000254%	393,306

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.Ile565Val
Coding: c.1693A>G
MANE Select: NM_000245
dbSNP: rs745479104
Type: single nucleotide variant
Location: chr7:116741017 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 565: a β-strand; the ipt/tig 1 domain

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

Disease context

Papillary renal cell carcinoma type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma hereditary neoplastic syndrome

Similar variants

MET p.Ile565Thr Uncertain significance ★★ same residue
MET p.Ile565Met Uncertain significance ★ ⚠ same residue
MET p.Ile565Ser 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

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-ile565val (accessed [today's date]).

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