Is MET p.Pro392Thr (c.1174C>A) pathogenic?

MET p.Pro392Thr (c.1174C>A) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.086); Very rare (popmax 0.00017%, nfe); Associated with Papillary renal cell carcinoma type 1.

What condition is associated with MET p.Pro392Thr (c.1174C>A)?

MET p.Pro392Thr (c.1174C>A) is associated with Papillary renal cell carcinoma type 1, renal cell carcinoma, hepatocellular carcinoma (ClinVar).

How common is MET p.Pro392Thr (c.1174C>A) in the general population?

MET p.Pro392Thr (c.1174C>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MET p.Pro392Thr (c.1174C>A)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

MET p.Pro392Thr

c.1174C>A · rs886061943 · VCV358684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Papillary renal cell carcinoma type 1

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -5.55	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 6.1	GERP 1.9, phastCons 1
Overall
CADD	21.0	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 0.00017% European (non-Finnish) · 2/1,178,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000207% 3/1,451,150 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,166
European (non-Finnish)grpmax	0.00017%	589,018

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro392Thr
Coding: c.1174C>A
MANE Select: NM_000245
dbSNP: rs886061943
Type: single nucleotide variant
Location: chr7:116700258 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 392: a β-strand; the sema domain; a disulfide bond

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

Disease context

Papillary renal cell carcinoma type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma hepatocellular carcinoma osteofibrous dysplasia autosomal recessive nonsyndromic hearing loss 97 hereditary neoplastic syndrome

Similar variants

MET p.Pro392His 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-pro392thr (accessed [today's date]).

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