Is VCAN p.Asp859= (c.2577T>C) pathogenic?

VCAN p.Asp859= (c.2577T>C) is classified Likely benign in VCAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.02%, amr).

How common is VCAN p.Asp859= (c.2577T>C) in the general population?

VCAN p.Asp859= (c.2577T>C) is ultra-rare (popmax 0.02%, amr) (gnomAD).

VCAN p.Asp859=

c.2577T>C · rs192605774 · VCV1408785

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, 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 -2.3	GERP -4.8
Overall
CADD	0.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00118% 19/1,614,152 alleles · ultra-rare exomes 14/1,461,820 · genomes 5/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
European (non-Finnish)	0.000593%	168,572

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.Asp859=
Coding: c.2577T>C
MANE Select: NM_004385
dbSNP: rs192605774
Type: single nucleotide variant
Location: chr5:83520883 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 859: the 'gag-alpha (glucosaminoglycan attachment domain)' region

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

Similar variants

VCAN p.Asp859Gly 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-asp859 (accessed [today's date]).

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