Is VCAN p.Ser740= (c.2220T>C) pathogenic?

VCAN p.Ser740= (c.2220T>C) is classified Benign/Likely benign in VCAN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Rare (popmax 0.323%, eas); Associated with vitreoretinal degeneration.

What condition is associated with VCAN p.Ser740= (c.2220T>C)?

VCAN p.Ser740= (c.2220T>C) is associated with vitreoretinal degeneration (ClinVar).

How common is VCAN p.Ser740= (c.2220T>C) in the general population?

VCAN p.Ser740= (c.2220T>C) is rare (popmax 0.323%, eas) (gnomAD).

VCAN p.Ser740=

c.2220T>C · rs201834775 · VCV354404

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.323%, eas)

Conditions

vitreoretinal degeneration

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.093	GERP -4.2
Overall
CADD	1.757	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.323% East Asian · 145/44,870 alleles

Filtering AF 0.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.264%

Overall 0.0133% 214/1,614,064 alleles · rare exomes 183/1,461,722 · genomes 31/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.323%	309
South Asian	0.0494%	2,024
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.00333%	30,002

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.Ser740=
Coding: c.2220T>C
MANE Select: NM_004385
dbSNP: rs201834775
Type: single nucleotide variant
Location: chr5:83520526 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 740: the 'gag-alpha (glucosaminoglycan attachment domain)' region

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

Disease context

vitreoretinal degeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VCAN p.Ser740Ala Uncertain significance ★ ⚠ same residue
VCAN p.Ser740Phe Uncertain significance ★ ⚠ same residue
VCAN c.*905A>G Uncertain significance ★★ same condition
VCAN p.Ala2446Val Uncertain significance ★★ ⚠ same condition
VCAN p.Arg1431His Uncertain significance ★★ ⚠ same condition
VCAN p.Glu2277Lys Uncertain significance ★★ ⚠ same condition
VCAN p.Gly1068Ser Uncertain significance ★★ ⚠ same condition
VCAN p.Gly2758Cys 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-ser740 (accessed [today's date]).

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