Is CBS p.His513= (c.1539C>T) pathogenic?

CBS p.His513= (c.1539C>T) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-26). Ultra-rare (popmax 0.0211%, afr); Associated with CBS-related disorder.

What condition is associated with CBS p.His513= (c.1539C>T)?

CBS p.His513= (c.1539C>T) is associated with CBS-related disorder, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.His513= (c.1539C>T) in the general population?

CBS p.His513= (c.1539C>T) is ultra-rare (popmax 0.0211%, afr) (gnomAD).

CBS p.His513=

c.1539C>T · rs187828882 · VCV212835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0211%, afr)

Conditions

CBS-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.343	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -2.2
Overall
CADD	1.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0211% African / African-American · 1/4,734 alleles

Overall 0.00321% 5/155,806 alleles · ultra-rare exomes 5/154,312 · genomes 0/1,494 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0387%	2,582
African / African-Americangrpmax	0.0211%	4,734
South Asian	0.00323%	30,998

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His513=
Coding: c.1539C>T
MANE Select: NM_000071
dbSNP: rs187828882
Type: single nucleotide variant
Location: chr21:43056816 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 513: a β-strand

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

Disease context

CBS-related disorder

Also linked: connective tissue disorder familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.His513Arg Uncertain significance ★ ⚠ same residue
CBS p.His513Gln Uncertain significance ★ ⚠ same residue
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.209+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala114Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala158Val Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala288Thr 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-his513 (accessed [today's date]).

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