Is MET p.Pro991Ser (c.2971C>T) pathogenic?

MET p.Pro991Ser (c.2971C>T) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.4417); Ultra-rare (popmax 0.0423%, eas); Associated with osteofibrous dysplasia.

What condition is associated with MET p.Pro991Ser (c.2971C>T)?

MET p.Pro991Ser (c.2971C>T) is associated with osteofibrous dysplasia, renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Pro991Ser (c.2971C>T) in the general population?

MET p.Pro991Ser (c.2971C>T) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

How is Osteofibrous dysplasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MET p.Pro991Ser (c.2971C>T)?

AlphaMissense predicts ambiguous (score 0.4417) — an in-silico prediction, not a clinical call.

MET p.Pro991Ser

c.2971C>T · rs768678989 · VCV411918

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4417 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Conditions

osteofibrous dysplasia

Computational evidence

Protein change
AlphaMissense	0.4417	ambiguous
REVEL	0.361	indeterminate
SaProt	LLR -4.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1, phastCons 1
Overall
CADD	24.8	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 0.0423% East Asian · 19/44,866 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.0013% 19/1,461,624 alleles · ultra-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.Pro991Ser
Coding: c.2971C>T
MANE Select: NM_000245
dbSNP: rs768678989
Type: single nucleotide variant
Location: chr7:116771932 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 991: a UniProt-annotated variant site (in osfd; loss of cbl-mediated destabilization); a UniProt-annotated variant site (in gastric cancer; prolonged tyrosine phosphorylation in response to hgf/sf; transforming activity in athymic nude mice)

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

Disease context

osteofibrous dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma hereditary neoplastic syndrome

For Osteofibrous dysplasia (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

MET p.Pro991Leu 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-pro991ser (accessed [today's date]).

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