Is CBS p.Met89Lys (c.266T>A) pathogenic?

CBS p.Met89Lys (c.266T>A) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-01). AlphaMissense: likely pathogenic (0.9195); Very rare (popmax 0.00131%, nfe).

How common is CBS p.Met89Lys (c.266T>A) in the general population?

CBS p.Met89Lys (c.266T>A) is very rare (popmax 0.00131%, nfe) (gnomAD).

What do computational predictors say about CBS p.Met89Lys (c.266T>A)?

AlphaMissense predicts likely pathogenic (score 0.9195) — an in-silico prediction, not a clinical call.

CBS p.Met89Lys

c.266T>A · rs772450760 · VCV212875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9195 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00131%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9195	likely pathogenic
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -10.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00131% European (non-Finnish) · 3/229,816 alleles

Filtering AF 0.000347% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.6e-05%

Overall 0.000797% 3/376,238 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: CBS
Protein: p.Met89Lys
Coding: c.266T>A
MANE Select: NM_000071
dbSNP: rs772450760
Type: single nucleotide variant
Location: chr21:43068559 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 89: a β-strand

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

Similar variants

CBS p.Met89Leu Uncertain significance ★ ⚠ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same type
CBS c.1223+1G>T Pathogenic ★★ same type
CBS c.1224-2A>C Pathogenic ★★ same type
CBS c.1358+1G>A Pathogenic ★★ same type
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same type
CBS c.1468-1G>A Likely pathogenic ★★ same type
CBS c.1552+1G>A Pathogenic/Likely pathogenic ★★ same type

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/cbs-p-met89lys (accessed [today's date]).

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