Is MET p.Asn635Ser (c.1904A>G) pathogenic?

MET p.Asn635Ser (c.1904A>G) is classified Uncertain significance in MET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-10). AlphaMissense: likely benign (0.0794); Very rare (popmax 0.005%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MET p.Asn635Ser (c.1904A>G)?

MET p.Asn635Ser (c.1904A>G) is associated with hereditary neoplastic syndrome, renal cell carcinoma (ClinVar).

How common is MET p.Asn635Ser (c.1904A>G) in the general population?

MET p.Asn635Ser (c.1904A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MET p.Asn635Ser (c.1904A>G)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

MET p.Asn635Ser

c.1904A>G · rs773826297 · VCV411877

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 0.52, phastCons 1
Overall
CADD	21.5	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

Grpmax group 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000479% 7/1,461,536 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.000169%	589,974

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.Asn635Ser
Coding: c.1904A>G
MANE Select: NM_000245
dbSNP: rs773826297
Type: single nucleotide variant
Location: chr7:116757478 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.28 · 130 PDB
Residue 635: a β-strand; the ipt/tig 1 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

Similar variants

MET p.Asn635= Benign/Likely benign ★★ same residue
MET p.Asn635Ile Uncertain significance ★ ⚠ same residue
MET p.Asn635Lys 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

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-asn635ser (accessed [today's date]).

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