Is MET p.Phe253Cys (c.758T>G) pathogenic?

MET p.Phe253Cys (c.758T>G) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-28). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Phe253Cys (c.758T>G)?

MET p.Phe253Cys (c.758T>G) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Phe253Cys (c.758T>G) in the general population?

MET p.Phe253Cys (c.758T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MET p.Phe253Cys (c.758T>G)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

MET p.Phe253Cys

c.758T>G · rs752495532 · VCV2453406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic · top 8% in MET
REVEL	0.756	pathogenic-leaning
SaProt	LLR -15.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Overall
CADD	26.8	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 8.47e-05% European (non-Finnish) · 1/1,179,976 alleles

Overall 6.2e-05% 1/1,614,118 alleles · very rare exomes 1/1,461,806 · genomes 0/152,312 · 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.Phe253Cys
Coding: c.758T>G
MANE Select: NM_000245
dbSNP: rs752495532
Type: single nucleotide variant
Location: chr7:116699842 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 253: a β-strand; the sema domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma

Similar variants

MET p.Phe253Leu Uncertain significance ★ ⚠ same residue
MET p.Phe253= Likely benign ★ 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
MET c.1392+1G>T 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-phe253cys (accessed [today's date]).

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