Is VCAN p.Pro53Ser (c.157C>T) pathogenic?

VCAN p.Pro53Ser (c.157C>T) is classified Conflicting classifications of pathogenicity in VCAN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.147); Ultra-rare (popmax 0.0164%, mid); Associated with vitreoretinal degeneration.

What condition is associated with VCAN p.Pro53Ser (c.157C>T)?

VCAN p.Pro53Ser (c.157C>T) is associated with vitreoretinal degeneration, Wagner disease (ClinVar).

How common is VCAN p.Pro53Ser (c.157C>T) in the general population?

VCAN p.Pro53Ser (c.157C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about VCAN p.Pro53Ser (c.157C>T)?

AlphaMissense predicts likely benign (score 0.147) — an in-silico prediction, not a clinical call.

VCAN p.Pro53Ser

c.157C>T · rs201466502 · VCV843872

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.147 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

vitreoretinal degeneration

Computational evidence

Protein change
AlphaMissense	0.147	likely benign
REVEL	0.076	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 6,912 bp · p 0.48 · regional, not allelic
Overall
CADD	15.21	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0124% 200/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.0153%	6,519
Remaining individualsnot grpmax-eligible	0.0144%	6,943
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402
African / African-American	0.00401%	24,964
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.00156%	64,022

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.Pro53Ser
Coding: c.157C>T
MANE Select: NM_004385
dbSNP: rs201466502
Type: single nucleotide variant
Location: chr5:83490184 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 53: the ig-like v-type domain; a disulfide bond

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

Disease context

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

Also linked: Wagner disease

Similar variants

VCAN p.Pro53= Likely benign ★ same residue
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

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-pro53ser (accessed [today's date]).

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