Is CBS p.Lys108fs (c.323del) pathogenic?

CBS p.Lys108fs (c.323del) is classified Likely pathogenic in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-20). Very rare (popmax 0.00265%, eas); Associated with classic homocystinuria.

What condition is associated with CBS p.Lys108fs (c.323del)?

CBS p.Lys108fs (c.323del) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Lys108fs (c.323del) in the general population?

CBS p.Lys108fs (c.323del) is very rare (popmax 0.00265%, eas) (gnomAD).

CBS p.Lys108fs

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.323del · rs1294996414 · VCV2680411

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00265%, eas)

Conditions

classic homocystinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP 1.5, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00265% East Asian · 1/37,758 alleles

Overall 0.000144% 1/693,050 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.Lys108fs
Coding: c.323del
MANE Select: NM_000071
dbSNP: rs1294996414
Type: Deletion
Location: chr21:43066371 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 108: a β-strand

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 c.209+1_209+8del Likely pathogenic ★★ same condition
CBS c.209+1del Pathogenic ★★ same condition
CBS c.667-14_667-7del Pathogenic/Likely pathogenic ★★ same condition
CBS c.738del Pathogenic ★★ same condition
CBS p.Arg161fs Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg51fs Pathogenic/Likely pathogenic ★★ same condition
CBS p.Asn194fs Pathogenic/Likely pathogenic ★★ same condition
CBS p.Leu230fs 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-lys108fs (accessed [today's date]).

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