Is VCAN p.Val83= (c.249C>A) pathogenic?

VCAN p.Val83= (c.249C>A) is classified Likely benign in VCAN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-14). Very rare (popmax 0.00814%, nfe); Associated with Wagner disease.

What condition is associated with VCAN p.Val83= (c.249C>A)?

VCAN p.Val83= (c.249C>A) is associated with Wagner disease, vitreoretinal degeneration (ClinVar).

How common is VCAN p.Val83= (c.249C>A) in the general population?

VCAN p.Val83= (c.249C>A) is very rare (popmax 0.00814%, nfe) (gnomAD).

How is Wagner disease inherited?

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

VCAN p.Val83=

c.249C>A · rs751640388 · VCV905572

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00814%, nfe)

Conditions

Wagner disease

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 -0.41	GERP -4.5, phastCons 0.14
Overall
CADD	3.736	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00814% European (non-Finnish) · 96/1,180,048 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00626% 101/1,614,186 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00814%	12,292
Remaining individualsnot grpmax-eligible	0.0048%	20,837
African / African-American	0.00266%	37,524

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.Val83=
Coding: c.249C>A
MANE Select: NM_004385
dbSNP: rs751640388
Type: single nucleotide variant
Location: chr5:83490276 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 83: the ig-like v-type domain

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

Disease context

Wagner disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: vitreoretinal degeneration

For Wagner disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

VCAN c.4004-1G>A Pathogenic ★★ same condition
VCAN c.4004-2A>C Pathogenic ★★ same condition
VCAN c.4004-2A>G Pathogenic ★★ same condition
VCAN c.4004-5T>C Pathogenic ★★ same condition
VCAN c.9265+1G>C Pathogenic ★★ same condition
VCAN c.9266-5G>A Uncertain significance ★★ same condition
VCAN c.*905A>G Uncertain significance ★★ same condition
VCAN p.Ala2446Val Uncertain significance ★★ ⚠ 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/vcan-p-val83 (accessed [today's date]).

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