Is MET p.Ala411= (c.1233G>A) pathogenic?

MET p.Ala411= (c.1233G>A) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.028%, afr); Associated with renal cell carcinoma.

What condition is associated with MET p.Ala411= (c.1233G>A)?

MET p.Ala411= (c.1233G>A) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Ala411= (c.1233G>A) in the general population?

MET p.Ala411= (c.1233G>A) is ultra-rare (popmax 0.028%, afr) (gnomAD).

MET p.Ala411=

c.1233G>A · rs374081963 · VCV132773

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

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 -2.4	GERP -3.5
Overall
CADD	1.718	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/75,040 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00359% 58/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,573
Middle Eastern	0.0165%	6,060
Admixed American	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00246%	40,688
South Asian	0.0011%	91,078

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.Ala411=
Coding: c.1233G>A
MANE Select: NM_000245
dbSNP: rs374081963
Type: single nucleotide variant
Location: chr7:116731700 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 411: 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: hereditary neoplastic syndrome

Similar variants

MET p.Ala411Thr Uncertain significance ★★ ⚠ same residue
MET p.Ala411Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Ala411Val 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-ala411 (accessed [today's date]).

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