Is MET p.Ser548Leu (c.1643C>T) pathogenic?

MET p.Ser548Leu (c.1643C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-03). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.00329%, sas); Associated with renal cell carcinoma.

What condition is associated with MET p.Ser548Leu (c.1643C>T)?

MET p.Ser548Leu (c.1643C>T) is associated with renal cell carcinoma, osteofibrous dysplasia, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ser548Leu (c.1643C>T) in the general population?

MET p.Ser548Leu (c.1643C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about MET p.Ser548Leu (c.1643C>T)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

MET p.Ser548Leu

c.1643C>T · rs767715328 · VCV485767

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.08	GERP -3.6
Overall
CADD	12.37	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,060 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000496% 8/1,613,718 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,353
Admixed American	0.00167%	59,984
European (non-Finnish)	0.000339%	294,997

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.Ser548Leu
Coding: c.1643C>T
MANE Select: NM_000245
dbSNP: rs767715328
Type: single nucleotide variant
Location: chr7:116740967 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 548: an α-helix; a disulfide bond

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: osteofibrous dysplasia hereditary neoplastic syndrome

Similar variants

MET p.Ser548= Benign/Likely benign ★★ same residue
MET p.Ser548Trp 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
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-ser548leu (accessed [today's date]).

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