Is VCAN p.Pro2500Ala (c.7498C>G) pathogenic?

VCAN p.Pro2500Ala (c.7498C>G) is classified Conflicting classifications of pathogenicity in VCAN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0636); Rare (popmax 0.115%, mid); Associated with Inborn genetic diseases.

What condition is associated with VCAN p.Pro2500Ala (c.7498C>G)?

VCAN p.Pro2500Ala (c.7498C>G) is associated with Inborn genetic diseases (ClinVar).

How common is VCAN p.Pro2500Ala (c.7498C>G) in the general population?

VCAN p.Pro2500Ala (c.7498C>G) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about VCAN p.Pro2500Ala (c.7498C>G)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

VCAN p.Pro2500Ala

c.7498C>G · rs766300338 · VCV963154

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.112	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 0.12	GERP -0.95
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.23 · regional, not allelic
Overall
CADD	2.616	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 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00366% 59/1,613,796 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Admixed American	0.02%	4,997
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
African / African-American	0.00267%	37,442
European (non-Finnish)	0.00229%	43,702
South Asian	0.0011%	91,058

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.Pro2500Ala
Coding: c.7498C>G
MANE Select: NM_004385
dbSNP: rs766300338
Type: single nucleotide variant
Location: chr5:83540501 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 2500: the 'gag-beta' region; the 'disordered' 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.Pro2500Ser Uncertain significance ★ ⚠ same residue
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

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-pro2500ala (accessed [today's date]).

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