Is CBS p.Asp133Asn (c.397G>A) pathogenic?

CBS p.Asp133Asn (c.397G>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0659); Ultra-rare (popmax 0.0161%, sas); Associated with connective tissue disorder.

What condition is associated with CBS p.Asp133Asn (c.397G>A)?

CBS p.Asp133Asn (c.397G>A) is associated with connective tissue disorder, classic homocystinuria, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Asp133Asn (c.397G>A) in the general population?

CBS p.Asp133Asn (c.397G>A) is ultra-rare (popmax 0.0161%, sas) (gnomAD).

What do computational predictors say about CBS p.Asp133Asn (c.397G>A)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

CBS p.Asp133Asn

c.397G>A · rs539326697 · VCV212844

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.3, phastCons 0.021
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	15.86	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 0.0161% South Asian · 12/74,690 alleles

Filtering AF 0.00924% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00724%

Overall 0.00141% 15/1,063,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0161%	6,224
East Asian	0.00236%	42,366
European (non-Finnish)	0.000269%	372,130

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.Asp133Asn
Coding: c.397G>A
MANE Select: NM_000071
dbSNP: rs539326697
Type: single nucleotide variant
Location: chr21:43066297 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CBS p.Asp133= 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-asp133asn (accessed [today's date]).

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