Is MET p.Ser435= (c.1305C>T) pathogenic?

MET p.Ser435= (c.1305C>T) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). Very rare (popmax 0.005%, amr); Associated with renal cell carcinoma.

What condition is associated with MET p.Ser435= (c.1305C>T)?

MET p.Ser435= (c.1305C>T) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ser435= (c.1305C>T) in the general population?

MET p.Ser435= (c.1305C>T) is very rare (popmax 0.005%, amr) (gnomAD).

MET p.Ser435=

c.1305C>T · rs762520351 · VCV485751

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, 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 0.01	GERP -3.5, phastCons 0.52
Overall
CADD	10.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,978 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000805% 13/1,614,006 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,993
African / African-American	0.00267%	37,465
European (non-Finnish)	0.000678%	147,499

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.Ser435=
Coding: c.1305C>T
MANE Select: NM_024755 · reported on NM_000245
dbSNP: rs762520351
Type: single nucleotide variant
Location: chr7:116731772 (GRCh38)
Structure: AlphaFold pLDDT 52.38
Residue 435: the rrm 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.Ser435Cys Uncertain significance ★★ ⚠ same residue
MET p.Ser435Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Ser435Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Ser435Arg 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

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-ser435 (accessed [today's date]).

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