Is MET p.Asp100His (c.298G>C) pathogenic?

MET p.Asp100His (c.298G>C) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1549); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 97.

What condition is associated with MET p.Asp100His (c.298G>C)?

MET p.Asp100His (c.298G>C) is associated with autosomal recessive nonsyndromic hearing loss 97, renal cell carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MET p.Asp100His (c.298G>C) in the general population?

MET p.Asp100His (c.298G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MET p.Asp100His (c.298G>C)?

AlphaMissense predicts likely benign (score 0.1549) — an in-silico prediction, not a clinical call.

MET p.Asp100His

c.298G>C · rs1554378400 · VCV485765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1549 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 97

Computational evidence

Protein change
AlphaMissense	0.1549	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.20	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 1.7	GERP -1.2, phastCons 1
Overall
CADD	18.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Asp100His
Coding: c.298G>C
MANE Select: NM_000245
dbSNP: rs1554378400
Type: single nucleotide variant
Location: chr7:116699382 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 100: a disulfide bond; the sema domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 97 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal cell carcinoma hereditary neoplastic syndrome

Similar variants

MET p.Asp100= Likely benign ★★ same residue
MET p.Asp100Gly Uncertain significance ★ ⚠ same residue
MET p.Asp100Asn 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

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-asp100his (accessed [today's date]).

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