Is MET p.Asp1228= (c.3684C>T) pathogenic?

MET p.Asp1228= (c.3684C>T) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-22). Very rare (popmax 0.00667%, amr); Associated with renal cell carcinoma.

What condition is associated with MET p.Asp1228= (c.3684C>T)?

MET p.Asp1228= (c.3684C>T) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Asp1228= (c.3684C>T) in the general population?

MET p.Asp1228= (c.3684C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

MET p.Asp1228=

c.3684C>T · rs786201612 · VCV184678

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -5.9
Overall
CADD	2.834	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

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

Overall 0.000372% 6/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Asp1228=
Coding: c.3684C>T
MANE Select: NM_000245
dbSNP: rs786201612
Type: single nucleotide variant
Location: chr7:116783355 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 1228: the 'interaction with ranbp9' region; a turn; a UniProt-annotated variant site (in rccp; somatic mutation); a UniProt-annotated variant site (in rccp; germline mutation); the protein kinase 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.Asp1228Asn Uncertain significance ★ ⚠ same residue
MET p.Asp1228Glu Uncertain significance ★ ⚠ same residue
MET p.Asp1228Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-asp1228 (accessed [today's date]).

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