Is CBS p.Arg491His (c.1472G>A) pathogenic?

CBS p.Arg491His (c.1472G>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-02-21). AlphaMissense: likely benign (0.0634); Ultra-rare (popmax 0.0209%, afr); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Arg491His (c.1472G>A)?

CBS p.Arg491His (c.1472G>A) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, classic homocystinuria, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Arg491His (c.1472G>A) in the general population?

CBS p.Arg491His (c.1472G>A) is ultra-rare (popmax 0.0209%, afr) (gnomAD).

What do computational predictors say about CBS p.Arg491His (c.1472G>A)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

CBS p.Arg491His

c.1472G>A · rs747419767 · VCV263326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -5.28	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 -13	GERP -1.9
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	0.001	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 0.0209% African / African-American · 1/4,794 alleles

Overall 0.00127% 2/157,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0209%	4,794
Remaining individualsnot grpmax-eligible	0.0125%	7,998

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.Arg491His
Coding: c.1472G>A
MANE Select: NM_000071
dbSNP: rs747419767
Type: single nucleotide variant
Location: chr21:43056883 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 491: a UniProt-annotated variant site (in cbsd; linked with c-369); a β-strand

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 familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Arg491Cys Uncertain significance ★★ ⚠ 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-arg491his (accessed [today's date]).

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