Is VCAN p.Pro3097Arg (c.9290C>G) pathogenic?

VCAN p.Pro3097Arg (c.9290C>G) is classified Uncertain significance in VCAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: likely pathogenic (0.7091); Very rare (popmax 0.00267%, afr).

How common is VCAN p.Pro3097Arg (c.9290C>G) in the general population?

VCAN p.Pro3097Arg (c.9290C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about VCAN p.Pro3097Arg (c.9290C>G)?

AlphaMissense predicts likely pathogenic (score 0.7091) — an in-silico prediction, not a clinical call.

VCAN p.Pro3097Arg

c.9290C>G · VCV3654458

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.7091	likely pathogenic · top 10% in VCAN
REVEL	0.8	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.23 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,906 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,942 alleles · very rare exomes 1/1,461,782 · genomes 1/152,160 · joint denominator

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.Pro3097Arg
Coding: c.9290C>G
MANE Select: NM_004385
Type: single nucleotide variant
Location: chr5:83545561 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 3097: the egf-like 1 domain

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

Similar variants

VCAN p.Pro3097Leu Uncertain significance ★★ ⚠ same residue
VCAN p.Pro3097= Benign/Likely benign ★★ 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

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-pro3097arg (accessed [today's date]).

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