Is CBS p.Leu230Gln (c.689T>A) pathogenic?

CBS p.Leu230Gln (c.689T>A) is classified Likely pathogenic in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: ambiguous (0.3987); Absent from gnomAD v4.1; Associated with classic homocystinuria.

What condition is associated with CBS p.Leu230Gln (c.689T>A)?

CBS p.Leu230Gln (c.689T>A) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Leu230Gln (c.689T>A) in the general population?

CBS p.Leu230Gln (c.689T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Leu230Gln (c.689T>A)?

AlphaMissense predicts ambiguous (score 0.3987) — an in-silico prediction, not a clinical call.

CBS p.Leu230Gln

Q: How is Homocystinuria due to cystathionine beta-synthase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.689T>A · rs1411597530 · VCV2680398

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.3987	ambiguous
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -6.69	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 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	26.5	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

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: CBS
Protein: p.Leu230Gln
Coding: c.689T>A
MANE Select: NM_000071
dbSNP: rs1411597530
Type: single nucleotide variant
Location: chr21:43065250 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 230: an α-helix

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

Disease context

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

For Homocystinuria due to cystathionine beta-synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CBS p.Leu230fs Pathogenic ★★ same residue
CBS p.Leu230= Likely benign ★ 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

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-leu230gln (accessed [today's date]).

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