Is VCAN p.Pro509Arg (c.1526C>G) pathogenic?

VCAN p.Pro509Arg (c.1526C>G) is classified Uncertain significance in VCAN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-23). AlphaMissense: likely benign (0.1327); Ultra-rare (popmax 0.0481%, afr); Associated with Inborn genetic diseases.

What condition is associated with VCAN p.Pro509Arg (c.1526C>G)?

VCAN p.Pro509Arg (c.1526C>G) is associated with Inborn genetic diseases (ClinVar).

How common is VCAN p.Pro509Arg (c.1526C>G) in the general population?

VCAN p.Pro509Arg (c.1526C>G) is ultra-rare (popmax 0.0481%, afr) (gnomAD).

What do computational predictors say about VCAN p.Pro509Arg (c.1526C>G)?

AlphaMissense predicts likely benign (score 0.1327) — an in-silico prediction, not a clinical call.

VCAN p.Pro509Arg

c.1526C>G · rs150340554 · VCV958173

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1327 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1327	likely benign
REVEL	0.31	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 0.61
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.23 · regional, not allelic
Overall
CADD	22.8	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 0.0481% African / African-American · 36/74,910 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00254% 41/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0481%	2,081
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,000

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.Pro509Arg
Coding: c.1526C>G
MANE Select: NM_004385
dbSNP: rs150340554
Type: single nucleotide variant
Location: chr5:83519832 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 509: the 'gag-alpha (glucosaminoglycan attachment domain)' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VCAN p.Ala1048Val Uncertain significance ★★ ⚠ same condition
VCAN p.Ala1228Thr Uncertain significance ★★ ⚠ same condition
VCAN p.Ala1314Gly Uncertain significance ★★ same condition
VCAN p.Ala1533Gly Uncertain significance ★★ ⚠ same condition
VCAN p.Ala2446Val Uncertain significance ★★ ⚠ same condition
VCAN p.Ala275Ser Uncertain significance ★★ ⚠ same condition
VCAN p.Ala2772Thr Uncertain significance ★★ ⚠ same condition
VCAN p.Ala2783Thr 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-pro509arg (accessed [today's date]).

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