Is VCAN p.Ala1533= (c.4599A>T) pathogenic?

VCAN p.Ala1533= (c.4599A>T) is classified Benign/Likely benign in VCAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0918%, amr).

How common is VCAN p.Ala1533= (c.4599A>T) in the general population?

VCAN p.Ala1533= (c.4599A>T) is ultra-rare (popmax 0.0918%, amr) (gnomAD).

VCAN p.Ala1533=

c.4599A>T · rs540210222 · VCV1166771

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0918%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -5.4
Overall
CADD	0.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0918% Admixed American · 55/59,922 alleles

Filtering AF 0.0723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0654%

Overall 0.00837% 135/1,613,868 alleles · ultra-rare exomes 116/1,461,544 · genomes 19/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0918%	1,089
Remaining individualsnot grpmax-eligible	0.0224%	4,463
European (non-Finnish)	0.00551%	18,153
African / African-American	0.00133%	75,038

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: VCAN
Protein: p.Ala1533=
Coding: c.4599A>T
MANE Select: NM_004385
dbSNP: rs540210222
Type: single nucleotide variant
Location: chr5:83537602 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 1533: the 'gag-beta' region; the 'disordered' region

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

Similar variants

VCAN p.Ala1533Gly Uncertain significance ★★ ⚠ same residue
VCAN c.4004-1G>A Pathogenic ★★ same type
VCAN c.4004-2A>C Pathogenic ★★ same type
VCAN c.4004-2A>G Pathogenic ★★ same type
VCAN c.4004-5T>C Pathogenic ★★ same type
VCAN c.9265+1G>C Pathogenic ★★ same type
VCAN c.9266-5G>A Uncertain significance ★★ same type
VCAN c.9493+5G>A Uncertain significance ★★ same type

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/vcan-p-ala1533 (accessed [today's date]).

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