Is VCAN p.Pro3313Ser (c.9937C>T) pathogenic?

VCAN p.Pro3313Ser (c.9937C>T) is classified Uncertain significance in VCAN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). AlphaMissense: likely pathogenic (0.9565); Ultra-rare (popmax 0.0165%, mid).

How common is VCAN p.Pro3313Ser (c.9937C>T) in the general population?

VCAN p.Pro3313Ser (c.9937C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about VCAN p.Pro3313Ser (c.9937C>T)?

AlphaMissense predicts likely pathogenic (score 0.9565) — an in-silico prediction, not a clinical call.

VCAN p.Pro3313Ser

c.9937C>T · rs1233521831 · VCV2814477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9565	likely pathogenic · top 4% in VCAN
REVEL	0.231	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 35 kb · p 9.3e-11 · regional, not allelic
Overall
CADD	24.8	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 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000186% 3/1,614,104 alleles · ultra-rare exomes 3/1,461,828 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	8.47e-05%	1,179,994

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.Pro3313Ser
Coding: c.9937C>T
MANE Select: NM_004385
dbSNP: rs1233521831
Type: single nucleotide variant
Location: chr5:83580036 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 3313: the sushi domain

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

Similar variants

VCAN p.Pro3313Leu Uncertain significance ★★ 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-pro3313ser (accessed [today's date]).

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