Is CBS p.Ile166Leu (c.496A>C) pathogenic?

CBS p.Ile166Leu (c.496A>C) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-06). AlphaMissense: likely benign (0.1853); Very rare (popmax 0.00494%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with CBS p.Ile166Leu (c.496A>C)?

CBS p.Ile166Leu (c.496A>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Ile166Leu (c.496A>C) in the general population?

CBS p.Ile166Leu (c.496A>C) is very rare (popmax 0.00494%, sas) (gnomAD).

What do computational predictors say about CBS p.Ile166Leu (c.496A>C)?

AlphaMissense predicts likely benign (score 0.1853) — an in-silico prediction, not a clinical call.

CBS p.Ile166Leu

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.496A>C · rs1982612017 · VCV1744446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00494%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1853	likely benign
REVEL	0.574	indeterminate
SaProt	LLR -12.27	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 -0.028	GERP -0.98, phastCons 0.8
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	19.8	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 0.00494% South Asian · 2/40,476 alleles

Filtering AF 0.000819% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000306%

Overall 0.00137% 4/292,830 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00494%	20,238
European (non-Finnish)	0.00124%	80,745

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.Ile166Leu
Coding: c.496A>C
MANE Select: NM_000071
dbSNP: rs1982612017
Type: single nucleotide variant
Location: chr21:43065651 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 166: a β-strand

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala114Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala288Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala331Glu Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg121His Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg125Gln Pathogenic ★★ ⚠ same condition
CBS p.Arg266Lys 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-ile166leu (accessed [today's date]).

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