Is MET p.Pro325Ser (c.973C>T) pathogenic?

MET p.Pro325Ser (c.973C>T) is classified Likely benign in MET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). AlphaMissense: ambiguous (0.5613); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Pro325Ser (c.973C>T)?

MET p.Pro325Ser (c.973C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MET p.Pro325Ser (c.973C>T) in the general population?

MET p.Pro325Ser (c.973C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MET p.Pro325Ser (c.973C>T)?

AlphaMissense predicts ambiguous (score 0.5613) — an in-silico prediction, not a clinical call.

MET p.Pro325Ser

c.973C>T · VCV4647673

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5613 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5613	ambiguous
REVEL	0.118	moderately benign-leaning
SaProt	LLR -9.07	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1, phastCons 1
Overall
CADD	21.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MET
Protein: p.Pro325Ser
Coding: c.973C>T
MANE Select: NM_000245
Type: single nucleotide variant
Location: chr7:116700057 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 325: an α-helix; 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

Similar variants

MET p.Pro325= Benign/Likely benign ★★ same residue
MET p.Pro325His Uncertain significance ★ ⚠ same residue
MET p.Pro325Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MET p.Pro325Thr 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

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-pro325ser (accessed [today's date]).

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