Is CBS p.Ala355Val (c.1064C>T) pathogenic?

CBS p.Ala355Val (c.1064C>T) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1293); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Ala355Val (c.1064C>T)?

CBS p.Ala355Val (c.1064C>T) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, classic homocystinuria (ClinVar).

How common is CBS p.Ala355Val (c.1064C>T) in the general population?

CBS p.Ala355Val (c.1064C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala355Val (c.1064C>T)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

CBS p.Ala355Val

c.1064C>T · rs772384826 · VCV499847

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 46,692)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -14.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 0.043, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	19.0	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

No allele count reported in gnomAD v4.1 (AN 46,692). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CBS
Protein: p.Ala355Val
Coding: c.1064C>T
MANE Select: NM_000071
dbSNP: rs772384826
Type: single nucleotide variant
Location: chr21:43060522 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 355: an α-helix; 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

Similar variants

CBS p.Ala355= Conflicting classifications of pathogenicity ★ same residue
CBS p.Ala355Pro Likely 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-ala355val (accessed [today's date]).

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