Is MET p.His476Arg (c.1427A>G) pathogenic?

MET p.His476Arg (c.1427A>G) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-09). AlphaMissense: ambiguous (0.4108); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.His476Arg (c.1427A>G)?

MET p.His476Arg (c.1427A>G) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.His476Arg (c.1427A>G) in the general population?

MET p.His476Arg (c.1427A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MET p.His476Arg (c.1427A>G)?

AlphaMissense predicts ambiguous (score 0.4108) — an in-silico prediction, not a clinical call.

MET p.His476Arg

c.1427A>G · rs2485637914 · VCV1772394

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4108 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4108	ambiguous
REVEL	0.458	indeterminate
SaProt	LLR -9.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MET
Protein: p.His476Arg
Coding: c.1427A>G
MANE Select: NM_000245
dbSNP: rs2485637914
Type: single nucleotide variant
Location: chr7:116739984 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 476: a β-strand; the sema 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.His476Leu Uncertain significance ★★ ⚠ same residue
MET p.His476= Likely benign ★★ same residue
MET p.His476Gln Uncertain significance ★ 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-his476arg (accessed [today's date]).

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