Is MET p.Ala48= (c.144G>A) pathogenic?

MET p.Ala48= (c.144G>A) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 5.56%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with renal cell carcinoma.

What condition is associated with MET p.Ala48= (c.144G>A)?

MET p.Ala48= (c.144G>A) is associated with renal cell carcinoma, hepatocellular carcinoma, osteofibrous dysplasia (ClinVar).

MET p.Ala48=

Q: How common is MET p.Ala48= (c.144G>A) in the general population?

MET p.Ala48= (c.144G>A) is common (popmax 5.56%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.144G>A · rs11762213 · VCV93567

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Common

common (popmax 5.56%, nfe) — too common for a highly-penetrant pathogenic allele

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 -5.1	GERP -3.5
Overall
CADD	0.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.56% European (non-Finnish) · 65,658/1,179,886 alleles

Filtering AF 5.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.51%

Overall 4.56% 73,654/1,613,846 alleles · common exomes 68,626/1,461,724 · genomes 5,028/152,122 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	5.56%	18
Amishnot grpmax-eligible	5.26%	19
Remaining individualsnot grpmax-eligible	3.96%	25
Ashkenazi Jewishnot grpmax-eligible	2.97%	34
Admixed American	2.92%	34
Middle Eastern	2.11%	47
Finnishnot grpmax-eligible	1.52%	66
South Asian	1.06%	94
African / African-American	1.03%	97
East Asian	0.00669%	14,957

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.Ala48=
Coding: c.144G>A
MANE Select: NM_000245
dbSNP: rs11762213
Type: single nucleotide variant
Location: chr7:116699228 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 48: the sema 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: hepatocellular carcinoma osteofibrous dysplasia autosomal recessive nonsyndromic hearing loss 97 hereditary neoplastic syndrome arthrogryposis, distal, IIa 11

Similar variants

MET p.Ala48Glu Uncertain significance ★ ⚠ same residue
MET p.Ala48Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Ala48Val 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

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-ala48 (accessed [today's date]).

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