Is MET p.Asp77Ala (c.230A>C) pathogenic?

MET p.Asp77Ala (c.230A>C) is classified Conflicting classifications of pathogenicity in MET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1163); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Asp77Ala (c.230A>C)?

MET p.Asp77Ala (c.230A>C) is associated with hereditary neoplastic syndrome, renal cell carcinoma, autosomal recessive nonsyndromic hearing loss 97 (ClinVar).

How common is MET p.Asp77Ala (c.230A>C) in the general population?

MET p.Asp77Ala (c.230A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MET p.Asp77Ala (c.230A>C)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

MET p.Asp77Ala

c.230A>C · rs761221409 · VCV947148

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -11.00	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.44, phastCons 1
Overall
CADD	20.1	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 0.000254% European (non-Finnish) · 3/1,179,956 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,756 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.Asp77Ala
Coding: c.230A>C
MANE Select: NM_000245
dbSNP: rs761221409
Type: single nucleotide variant
Location: chr7:116699314 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 77: 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: renal cell carcinoma autosomal recessive nonsyndromic hearing loss 97

Similar variants

MET p.Asp77= Likely benign ★★ same residue
MET p.Asp77Asn Conflicting classifications of pathogenicity ★ ⚠ 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-asp77ala (accessed [today's date]).

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