Is MET p.Ser458= (c.1374A>G) pathogenic?

MET p.Ser458= (c.1374A>G) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0223%, eas); Associated with Papillary renal cell carcinoma type 1.

What condition is associated with MET p.Ser458= (c.1374A>G)?

MET p.Ser458= (c.1374A>G) is associated with Papillary renal cell carcinoma type 1, renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ser458= (c.1374A>G) in the general population?

MET p.Ser458= (c.1374A>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

MET p.Ser458=

c.1374A>G · rs755165691 · VCV698969

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Conditions

Papillary renal cell carcinoma type 1

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 0.14	GERP -2.4, phastCons 0.13
Overall
CADD	6.817	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,898 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000805% 13/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,490
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	8.47e-05%	1,179,970

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.Ser458=
Coding: c.1374A>G
MANE Select: NM_024755 · reported on NM_000245
dbSNP: rs755165691
Type: single nucleotide variant
Location: chr7:116731841 (GRCh38)
Structure: AlphaFold pLDDT 52.38
Residue 458: the rrm domain; the 'disordered' region

Full MET gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Papillary renal cell carcinoma type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma 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-ser458 (accessed [today's date]).

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