Is MET p.Ser755Arg (c.2263A>C) pathogenic?

MET p.Ser755Arg (c.2263A>C) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.8603); Very rare (popmax 0.000254%, nfe); Associated with renal cell carcinoma.

What condition is associated with MET p.Ser755Arg (c.2263A>C)?

MET p.Ser755Arg (c.2263A>C) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ser755Arg (c.2263A>C) in the general population?

MET p.Ser755Arg (c.2263A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MET p.Ser755Arg (c.2263A>C)?

AlphaMissense predicts likely pathogenic (score 0.8603) — an in-silico prediction, not a clinical call.

MET p.Ser755Arg

c.2263A>C · rs981401332 · VCV1199923

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.8603	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -10.11	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 8.1	GERP 1.8, phastCons 1
Overall
CADD	23.9	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 0.000254% European (non-Finnish) · 3/1,179,446 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,250 alleles · very rare exomes 3/1,460,954 · genomes 0/152,296 · 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.Ser755Arg
Coding: c.2263A>C
MANE Select: NM_000245
dbSNP: rs981401332
Type: single nucleotide variant
Location: chr7:116758619 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 755: the ipt/tig 3 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.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
MET c.1392+3A>G Uncertain significance ★★ same condition
MET c.1392+5G>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-ser755arg (accessed [today's date]).

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