Is MET p.Leu78Phe (c.232C>T) pathogenic?

MET p.Leu78Phe (c.232C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-27). AlphaMissense: likely benign (0.2102); Very rare (popmax 0.00769%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Leu78Phe (c.232C>T)?

MET p.Leu78Phe (c.232C>T) is associated with hereditary neoplastic syndrome, hereditary papillary renal cell carcinoma, renal cell carcinoma (ClinVar).

How common is MET p.Leu78Phe (c.232C>T) in the general population?

MET p.Leu78Phe (c.232C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about MET p.Leu78Phe (c.232C>T)?

AlphaMissense predicts likely benign (score 0.2102) — an in-silico prediction, not a clinical call.

MET p.Leu78Phe

c.232C>T · rs766815155 · VCV1367069

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2102	likely benign
REVEL	0.477	indeterminate
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Overall
CADD	23.6	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 0.00769% South Asian · 7/91,084 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000479% 7/1,461,756 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.Leu78Phe
Coding: c.232C>T
MANE Select: NM_000245
dbSNP: rs766815155
Type: single nucleotide variant
Location: chr7:116699316 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 78: a turn; 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: hereditary papillary renal cell carcinoma renal cell carcinoma

Similar variants

MET p.Leu78Ile Uncertain significance ★ ⚠ same residue
MET p.Leu78= Likely benign ★ 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

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-leu78phe (accessed [today's date]).

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