Is MET p.Ser135= (c.405C>T) pathogenic?

MET p.Ser135= (c.405C>T) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Rare (popmax 0.125%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Ser135= (c.405C>T)?

MET p.Ser135= (c.405C>T) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Ser135= (c.405C>T) in the general population?

MET p.Ser135= (c.405C>T) is rare (popmax 0.125%, eas) (gnomAD).

MET p.Ser135=

c.405C>T · rs200494620 · VCV416926

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.125%, eas)

Conditions

hereditary neoplastic syndrome

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 -5.8	GERP -3.5
Overall
CADD	5.936	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.125% East Asian · 56/44,878 alleles

Filtering AF 0.0986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00471% 76/1,613,942 alleles · rare exomes 72/1,461,734 · genomes 4/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.125%	801
Remaining individualsnot grpmax-eligible	0.0048%	20,831
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00136%	73,746

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.Ser135=
Coding: c.405C>T
MANE Select: NM_000245
dbSNP: rs200494620
Type: single nucleotide variant
Location: chr7:116699489 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 135: 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.Ser135Asn Uncertain significance ★★ ⚠ same residue
MET p.Ser135Cys 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
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-ser135 (accessed [today's date]).

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