Is MET p.Arg591Trp (c.1771C>T) pathogenic?

MET p.Arg591Trp (c.1771C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1265); Ultra-rare (popmax 0.0454%, afr); Associated with renal cell carcinoma.

What condition is associated with MET p.Arg591Trp (c.1771C>T)?

MET p.Arg591Trp (c.1771C>T) is associated with renal cell carcinoma, breast carcinoma, squamous cell lung carcinoma (ClinVar).

How common is MET p.Arg591Trp (c.1771C>T) in the general population?

MET p.Arg591Trp (c.1771C>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

What do computational predictors say about MET p.Arg591Trp (c.1771C>T)?

AlphaMissense predicts likely benign (score 0.1265) — an in-silico prediction, not a clinical call.

MET p.Arg591Trp

c.1771C>T · rs45602940 · VCV134654

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1265 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.1265	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -4.60	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 6.5	GERP -0.71, phastCons 1
Overall
CADD	26.2	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 0.0454% African / African-American · 34/74,952 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00291% 47/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,204
Admixed American	0.005%	19,995
East Asian	0.00446%	22,433
South Asian	0.00329%	30,358
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000254%	393,324

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.Arg591Trp
Coding: c.1771C>T
MANE Select: NM_000245
dbSNP: rs45602940
Type: single nucleotide variant
Location: chr7:116755424 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 591: a β-strand; the ipt/tig 1 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: breast carcinoma squamous cell lung carcinoma autosomal recessive nonsyndromic hearing loss 97 hereditary neoplastic syndrome

Similar variants

MET p.Arg591= Likely benign ★★ same residue
MET p.Arg591Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Arg591Gly 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-arg591trp (accessed [today's date]).

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