Is CBS p.Arg266Lys (c.797G>A) pathogenic?

CBS p.Arg266Lys (c.797G>A) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.4026); Very rare (popmax 0.00271%, nfe); Associated with homocystinuria.

What condition is associated with CBS p.Arg266Lys (c.797G>A)?

CBS p.Arg266Lys (c.797G>A) is associated with homocystinuria, classic homocystinuria, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Arg266Lys (c.797G>A) in the general population?

CBS p.Arg266Lys (c.797G>A) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about CBS p.Arg266Lys (c.797G>A)?

AlphaMissense predicts ambiguous (score 0.4026) — an in-silico prediction, not a clinical call.

CBS p.Arg266Lys

c.797G>A · rs121964969 · VCV125

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

homocystinuria

Computational evidence

Protein change
AlphaMissense	0.4026	ambiguous
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -7.41	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	26.7	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 0.00271% European (non-Finnish) · 3/110,860 alleles

Filtering AF 0.000719% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000299%

Overall 0.00146% 3/205,802 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.Arg266Lys
Coding: c.797G>A
MANE Select: NM_000071
dbSNP: rs121964969
Type: single nucleotide variant
Location: chr21:43063931 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 266: an α-helix; a UniProt-annotated variant site (in cbsd); a UniProt-annotated variant site (in cbsd; mild form; decreased cystathionine beta-synthase activity; decreased homotetramer formation; no effect on heme-binding; decreased stability)

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

Disease context

homocystinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: classic homocystinuria familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Arg266Gly Likely pathogenic ★ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.1358+1G>A Pathogenic ★★ same condition
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBS c.1468-1G>A Likely pathogenic ★★ same condition
CBS c.1552+1G>A 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/cbs-p-arg266lys (accessed [today's date]).

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