Is MET p.Arg413His (c.1238G>A) pathogenic?

MET p.Arg413His (c.1238G>A) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.00549%, sas); Associated with renal cell carcinoma.

What condition is associated with MET p.Arg413His (c.1238G>A)?

MET p.Arg413His (c.1238G>A) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Arg413His (c.1238G>A) in the general population?

MET p.Arg413His (c.1238G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about MET p.Arg413His (c.1238G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

MET p.Arg413His

c.1238G>A · rs375391602 · VCV454180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal cell carcinoma

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.66	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 -0.16	GERP -0.97
Overall
CADD	16.68	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 0.00549% South Asian · 5/91,088 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00186% 30/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,459
Admixed American	0.00167%	59,982
European (non-Finnish)	0.00161%	62,104
Finnishnot grpmax-eligible	0.00156%	64,034

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.Arg413His
Coding: c.1238G>A
MANE Select: NM_000245
dbSNP: rs375391602
Type: single nucleotide variant
Location: chr7:116731705 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 413: 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.Arg413Cys Uncertain significance ★★ ⚠ same residue
MET p.Arg413Gly Uncertain significance ★ ⚠ same residue
MET p.Arg413Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Arg413Pro Uncertain significance ★ ⚠ same residue
MET p.Arg413= Benign ★ same residue
MET p.Arg413Ser Uncertain significance ⚠ same residue
MET p.His1094Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
MET p.Met1131Thr Pathogenic/Likely pathogenic ★★ 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-arg413his (accessed [today's date]).

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