Is CBS p.Leu136Pro (c.407T>C) pathogenic?

CBS p.Leu136Pro (c.407T>C) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.9586); Very rare (popmax 0.000249%, nfe); Associated with classic homocystinuria.

What condition is associated with CBS p.Leu136Pro (c.407T>C)?

CBS p.Leu136Pro (c.407T>C) is associated with classic homocystinuria, homocystinuria (ClinVar).

How common is CBS p.Leu136Pro (c.407T>C) in the general population?

CBS p.Leu136Pro (c.407T>C) is very rare (popmax 0.000249%, nfe) (gnomAD).

What do computational predictors say about CBS p.Leu136Pro (c.407T>C)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

CBS p.Leu136Pro

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.407T>C · rs775937459 · VCV2680403

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000249%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.9586	likely pathogenic ✓ concordant with ClinVar · top 8% in CBS
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -14.06	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 1.3, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.000249% European (non-Finnish) · 2/802,684 alleles

Filtering AF 4.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.6e-05%

Overall 0.000177% 2/1,131,792 alleles · very rare exomes 0/1,030,186 · genomes 2/101,606 · joint denominator

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.Leu136Pro
Coding: c.407T>C
MANE Select: NM_000071
dbSNP: rs775937459
Type: single nucleotide variant
Location: chr21:43066287 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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

Also linked: homocystinuria

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.Leu136= 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-leu136pro (accessed [today's date]).

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