Is VCAN p.Thr754= (c.2262A>T) pathogenic?

VCAN p.Thr754= (c.2262A>T) is classified Benign/Likely benign in VCAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-17). Rare (popmax 0.143%, afr).

How common is VCAN p.Thr754= (c.2262A>T) in the general population?

VCAN p.Thr754= (c.2262A>T) is rare (popmax 0.143%, afr) (gnomAD).

VCAN p.Thr754=

c.2262A>T · rs113094612 · VCV1170717

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.143%, afr)

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 0.39	GERP 0.034
Overall
CADD	2.347	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.143% African / African-American · 107/75,054 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00743% 120/1,614,072 alleles · rare exomes 53/1,461,718 · genomes 67/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.143%	701
Admixed American	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.0096%	10,418

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.Thr754=
Coding: c.2262A>T
MANE Select: NM_004385
dbSNP: rs113094612
Type: single nucleotide variant
Location: chr5:83520568 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 754: the 'gag-alpha (glucosaminoglycan attachment domain)' region

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

Similar variants

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
VCAN c.9493+5G>T 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-thr754 (accessed [today's date]).

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