Is MET p.Cys526Phe (c.1577G>T) pathogenic?

MET p.Cys526Phe (c.1577G>T) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.9359); Very rare (popmax 0.000124%); Associated with renal cell carcinoma.

What condition is associated with MET p.Cys526Phe (c.1577G>T)?

MET p.Cys526Phe (c.1577G>T) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Cys526Phe (c.1577G>T) in the general population?

MET p.Cys526Phe (c.1577G>T) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about MET p.Cys526Phe (c.1577G>T)?

AlphaMissense predicts likely pathogenic (score 0.9359) — an in-silico prediction, not a clinical call.

MET p.Cys526Phe

c.1577G>T · VCV4106777

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9359 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.9359	likely pathogenic
REVEL	0.625	indeterminate
SaProt	LLR -14.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000124%

Overall 0.000124% 2/1,614,154 alleles · very rare exomes 2/1,461,882 · genomes 0/152,272 · joint denominator

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.Cys526Phe
Coding: c.1577G>T
MANE Select: NM_000245
Type: single nucleotide variant
Location: chr7:116740901 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 526: an α-helix; a disulfide bond

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.Cys526Tyr Uncertain significance ★★ ⚠ same residue
MET p.Cys526= Uncertain significance ★ same residue
MET p.Cys526Ter 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-cys526phe (accessed [today's date]).

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