Is MET p.Arg469Pro (c.1406G>C) pathogenic?

MET p.Arg469Pro (c.1406G>C) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.5619); Very rare (popmax 0.000169%, nfe); Associated with renal cell carcinoma.

What condition is associated with MET p.Arg469Pro (c.1406G>C)?

MET p.Arg469Pro (c.1406G>C) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Arg469Pro (c.1406G>C) in the general population?

MET p.Arg469Pro (c.1406G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MET p.Arg469Pro (c.1406G>C)?

AlphaMissense predicts ambiguous (score 0.5619) — an in-silico prediction, not a clinical call.

MET p.Arg469Pro

c.1406G>C · rs752842662 · VCV1404739

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.5619	ambiguous
REVEL	0.676	pathogenic-leaning
SaProt	LLR -1.99	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	31.0	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 0.000169% European (non-Finnish) · 2/1,179,950 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,790 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	0.000169%	589,974

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg469Pro
Coding: c.1406G>C
MANE Select: NM_000245
dbSNP: rs752842662
Type: single nucleotide variant
Location: chr7:116739963 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 469: a β-strand; the sema domain

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: hereditary neoplastic syndrome

Similar variants

MET p.Arg469Gln Uncertain significance ★★ ⚠ same residue
MET p.Arg469Leu Uncertain significance ★★ same residue
MET p.Arg469Ter 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-arg469pro (accessed [today's date]).

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