Is VCAN p.Pro337Ala (c.1009C>G) pathogenic?

VCAN p.Pro337Ala (c.1009C>G) is classified Conflicting classifications of pathogenicity in VCAN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.109); Very rare (popmax 0.0084%, nfe); Associated with Inborn genetic diseases.

What condition is associated with VCAN p.Pro337Ala (c.1009C>G)?

VCAN p.Pro337Ala (c.1009C>G) is associated with Inborn genetic diseases, Wagner disease, vitreoretinal degeneration (ClinVar).

How common is VCAN p.Pro337Ala (c.1009C>G) in the general population?

VCAN p.Pro337Ala (c.1009C>G) is very rare (popmax 0.0084%, nfe) (gnomAD).

What do computational predictors say about VCAN p.Pro337Ala (c.1009C>G)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

VCAN p.Pro337Ala

c.1009C>G · rs199827515 · VCV906146

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0084%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.204	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 29 kb · p 6.4e-09 · regional, not allelic
Overall
CADD	24.5	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 0.0084% European (non-Finnish) · 99/1,178,092 alleles

Filtering AF 0.00704% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00653%

Overall 0.00652% 105/1,611,578 alleles · very rare exomes 96/1,459,430 · genomes 9/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0084%	11,900
Remaining individualsnot grpmax-eligible	0.00641%	15,597
Admixed American	0.00167%	59,924
African / African-American	0.00134%	74,852

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.Pro337Ala
Coding: c.1009C>G
MANE Select: NM_004385
dbSNP: rs199827515
Type: single nucleotide variant
Location: chr5:83512363 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 337: the link 2 domain

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

Also linked: Wagner disease vitreoretinal degeneration

Similar variants

VCAN p.Pro337Thr Uncertain significance ★ ⚠ 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-pro337ala (accessed [today's date]).

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