Is CBS p.Pro49Leu (c.146C>T) pathogenic?

CBS p.Pro49Leu (c.146C>T) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-05-12). AlphaMissense: likely benign (0.0874); Absent from gnomAD v4.1; Associated with Autosomal recessive CBS-related disorders.

What condition is associated with CBS p.Pro49Leu (c.146C>T)?

CBS p.Pro49Leu (c.146C>T) is associated with Autosomal recessive CBS-related disorders, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Pro49Leu (c.146C>T) in the general population?

CBS p.Pro49Leu (c.146C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Pro49Leu (c.146C>T)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

CBS p.Pro49Leu

c.146C>T · rs148865119 · VCV212872

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Autosomal recessive CBS-related disorders

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign ⚠ discordant with ClinVar
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -9.57	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.74, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	24.0	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.Pro49Leu
Coding: c.146C>T
MANE Select: NM_000071
dbSNP: rs148865119
Type: single nucleotide variant
Location: chr21:43072048 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 49: an α-helix; a UniProt-annotated variant site (in cbsd; decreased expression; no effect on cystathionine beta-synthase activity; increased homotetramer formation); the 'disordered' region

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

Disease context

Autosomal recessive CBS-related disorders

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

Similar variants

CBS p.Pro49= 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
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-pro49leu (accessed [today's date]).

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