Is CBS p.Cys52Tyr (c.155G>A) pathogenic?

CBS p.Cys52Tyr (c.155G>A) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.8785); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Cys52Tyr (c.155G>A)?

CBS p.Cys52Tyr (c.155G>A) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, classic homocystinuria (ClinVar).

How common is CBS p.Cys52Tyr (c.155G>A) in the general population?

CBS p.Cys52Tyr (c.155G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Cys52Tyr (c.155G>A)?

AlphaMissense predicts likely pathogenic (score 0.8785) — an in-silico prediction, not a clinical call.

CBS p.Cys52Tyr

c.155G>A · rs779777933 · VCV538697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8785 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.8785	likely pathogenic
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.74	donor gain · deltas
Pangolin	Δ0.67	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	35.0	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.Cys52Tyr
Coding: c.155G>A
MANE Select: NM_000071
dbSNP: rs779777933
Type: single nucleotide variant
Location: chr21:43072039 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 52: the 'disordered' region; a binding site

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

Similar variants

CBS p.Cys52Ser Likely pathogenic ★ ⚠ same residue
CBS p.Cys52Ter Pathogenic ★ 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-cys52tyr (accessed [today's date]).

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