Is MET p.Phe346= (c.1038C>T) pathogenic?

MET p.Phe346= (c.1038C>T) is classified Benign/Likely benign in MET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Very rare (popmax 0.00519%, nfe); Associated with renal cell carcinoma.

What condition is associated with MET p.Phe346= (c.1038C>T)?

MET p.Phe346= (c.1038C>T) is associated with renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Phe346= (c.1038C>T) in the general population?

MET p.Phe346= (c.1038C>T) is very rare (popmax 0.00519%, nfe) (gnomAD).

MET p.Phe346=

c.1038C>T · rs376235685 · VCV454175

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00519%, nfe)

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 -3.1	GERP -3.7
Overall
CADD	5.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00519% European (non-Finnish) · 61/1,176,182 alleles

Filtering AF 0.00411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00373%

Overall 0.00411% 66/1,605,490 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00519%	19,282
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,084
African / African-American	0.00269%	37,231
Remaining individualsnot grpmax-eligible	0.00161%	62,046
South Asian	0.00112%	89,404

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.Phe346=
Coding: c.1038C>T
MANE Select: NM_024755 · reported on NM_000245
dbSNP: rs376235685
Type: single nucleotide variant
Location: chr7:116700122 (GRCh38)
Structure: AlphaFold pLDDT 52.38
Residue 346: the 'disordered' region

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.Phe346Leu 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
MET c.1392+1G>T Uncertain significance ★★ same condition
MET c.1392+3A>G 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-phe346 (accessed [today's date]).

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