Is CBS p.Pro200Leu (c.599C>T) pathogenic?

CBS p.Pro200Leu (c.599C>T) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-04-22). AlphaMissense: likely benign (0.1528); Very rare (popmax 0.00863%, nfe); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Pro200Leu (c.599C>T)?

CBS p.Pro200Leu (c.599C>T) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, classic homocystinuria, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Pro200Leu (c.599C>T) in the general population?

CBS p.Pro200Leu (c.599C>T) is very rare (popmax 0.00863%, nfe) (gnomAD).

What do computational predictors say about CBS p.Pro200Leu (c.599C>T)?

AlphaMissense predicts likely benign (score 0.1528) — an in-silico prediction, not a clinical call.

CBS p.Pro200Leu

c.599C>T · rs758712880 · VCV642590

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00863%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.1528	likely benign
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -11.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
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 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · 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 0.00863% European (non-Finnish) · 21/243,358 alleles

Filtering AF 0.00574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0048%

Overall 0.00516% 23/445,636 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00863%	11,588
African / African-American	0.00558%	17,916
Remaining individualsnot grpmax-eligible	0.00412%	24,286

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.Pro200Leu
Coding: c.599C>T
MANE Select: NM_000071
dbSNP: rs758712880
Type: single nucleotide variant
Location: chr21:43065454 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 200: a β-strand; a UniProt-annotated variant site (in cbsd)

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

Disease context

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED — 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.Pro200= Conflicting classifications of pathogenicity ★ same residue
CBS p.Pro200Arg Uncertain significance ★ ⚠ 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-pro200leu (accessed [today's date]).

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