Is MET p.Phe258fs (c.774del) pathogenic?

MET p.Phe258fs (c.774del) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-22). Very rare (popmax 0.00667%, amr); Associated with renal cell carcinoma.

What condition is associated with MET p.Phe258fs (c.774del)?

MET p.Phe258fs (c.774del) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Phe258fs (c.774del) in the general population?

MET p.Phe258fs (c.774del) is very rare (popmax 0.00667%, amr) (gnomAD).

MET p.Phe258fs

c.774del · rs1281772042 · VCV1426999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

renal cell carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.66, phastCons 0.95
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00329% 5/152,172 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Phe258fs
Coding: c.774del
MANE Select: NM_000245
dbSNP: rs1281772042
Type: Deletion
Location: chr7:116699855 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 258: 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.Phe258Ser Uncertain significance ★ ⚠ same residue
MET p.Phe258= Likely benign ★ same residue
MET c.2265-42del Uncertain significance ★★ same condition
MET p.Gly1119del Uncertain significance ★★ same condition
MET p.His1052fs Uncertain significance ★★ same condition
MET p.Leu893fs Uncertain significance ★★ same condition
MET p.Met1fs Uncertain significance ★★ same condition
MET p.Pro356fs 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-phe258fs (accessed [today's date]).

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