Is VCAN p.Pro2500Ser (c.7498C>T) pathogenic?

VCAN p.Pro2500Ser (c.7498C>T) is classified Uncertain significance in VCAN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely benign (0.0713); Very rare (popmax 0.00212%, nfe).

How common is VCAN p.Pro2500Ser (c.7498C>T) in the general population?

VCAN p.Pro2500Ser (c.7498C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about VCAN p.Pro2500Ser (c.7498C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

VCAN p.Pro2500Ser

c.7498C>T · rs766300338 · VCV960514

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.105	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	2.837	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00212% European (non-Finnish) · 25/1,179,950 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,613,796 alleles · very rare exomes 23/1,461,710 · genomes 2/152,086 · 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.Pro2500Ser
Coding: c.7498C>T
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

Similar variants

VCAN p.Pro2500Ala Conflicting classifications of pathogenicity ★ ⚠ 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
VCAN c.9493+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-pro2500ser (accessed [today's date]).

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