Is VCAN p.Pro54Ser (c.160C>T) pathogenic?

VCAN p.Pro54Ser (c.160C>T) is classified Conflicting classifications of pathogenicity in VCAN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1697); Ultra-rare (popmax 0.075%, amr); Associated with Wagner disease.

What condition is associated with VCAN p.Pro54Ser (c.160C>T)?

VCAN p.Pro54Ser (c.160C>T) is associated with Wagner disease, vitreoretinal degeneration (ClinVar).

How common is VCAN p.Pro54Ser (c.160C>T) in the general population?

VCAN p.Pro54Ser (c.160C>T) is ultra-rare (popmax 0.075%, amr) (gnomAD).

How is Wagner disease inherited?

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

What do computational predictors say about VCAN p.Pro54Ser (c.160C>T)?

AlphaMissense predicts likely benign (score 0.1697) — an in-silico prediction, not a clinical call.

VCAN p.Pro54Ser

c.160C>T · rs140063016 · VCV860846

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Wagner disease

Computational evidence

Protein change
AlphaMissense	0.1697	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 6,912 bp · p 0.48 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.075% Admixed American · 45/60,014 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00601% 97/1,614,128 alleles · ultra-rare exomes 70/1,461,886 · genomes 27/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.075%	1,334
Remaining individualsnot grpmax-eligible	0.0112%	8,930
African / African-American	0.004%	25,006
European (non-Finnish)	0.00356%	28,096

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.Pro54Ser
Coding: c.160C>T
MANE Select: NM_004385
dbSNP: rs140063016
Type: single nucleotide variant
Location: chr5:83490187 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 54: 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-pro54ser (accessed [today's date]).

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