Is MET p.Cys385Arg (c.1153T>C) pathogenic?

MET p.Cys385Arg (c.1153T>C) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-17). AlphaMissense: likely pathogenic (0.9596); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Cys385Arg (c.1153T>C)?

MET p.Cys385Arg (c.1153T>C) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Cys385Arg (c.1153T>C) in the general population?

MET p.Cys385Arg (c.1153T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MET p.Cys385Arg (c.1153T>C)?

AlphaMissense predicts likely pathogenic (score 0.9596) — an in-silico prediction, not a clinical call.

MET p.Cys385Arg

c.1153T>C · rs1562884601 · VCV2453424

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9596	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	22.6	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 0.00223% East Asian · 1/44,840 alleles

Overall 0.000657% 1/152,226 alleles · very rare

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.Cys385Arg
Coding: c.1153T>C
MANE Select: NM_000245
dbSNP: rs1562884601
Type: single nucleotide variant
Location: chr7:116700237 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 385: a β-strand; the sema domain; a disulfide bond; a UniProt-annotated variant site (found in a case of cancer of unknown primary origin; uncertain significance; somatic mutation; the mutated receptor can sustain invasive cell growth in vitro)

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.Cys385Ser Uncertain significance ★★ ⚠ same residue
MET p.Cys385Tyr Uncertain significance ★★ ⚠ same residue
MET p.Cys385= 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

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-cys385arg (accessed [today's date]).

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