Is MET p.Ala411Thr (c.1231G>A) pathogenic?

MET p.Ala411Thr (c.1231G>A) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-08). AlphaMissense: likely benign (0.0723); Very rare (popmax 0.00266%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Ala411Thr (c.1231G>A)?

MET p.Ala411Thr (c.1231G>A) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Ala411Thr (c.1231G>A) in the general population?

MET p.Ala411Thr (c.1231G>A) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about MET p.Ala411Thr (c.1231G>A)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

MET p.Ala411Thr

c.1231G>A · rs752281264 · VCV1434428

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.76	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 7.6	GERP 0.89, phastCons 1
Overall
CADD	16.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00266% African / African-American · 2/75,054 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,796 alleles · very rare

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.Ala411Thr
Coding: c.1231G>A
MANE Select: NM_024755 · reported on NM_000245
dbSNP: rs752281264
Type: single nucleotide variant
Location: chr7:116731698 (GRCh38)
Structure: AlphaFold pLDDT 52.38
Residue 411: the rrm domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma

Similar variants

MET p.Ala411= Benign/Likely benign ★★ 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-ala411thr (accessed [today's date]).

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