Is VCAN p.Val720Ala (c.2159T>C) pathogenic?

VCAN p.Val720Ala (c.2159T>C) is classified Benign/Likely benign in VCAN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0967); Rare (popmax 0.395%, nfe); Associated with vitreoretinal degeneration.

What condition is associated with VCAN p.Val720Ala (c.2159T>C)?

VCAN p.Val720Ala (c.2159T>C) is associated with vitreoretinal degeneration (ClinVar).

How common is VCAN p.Val720Ala (c.2159T>C) in the general population?

VCAN p.Val720Ala (c.2159T>C) is rare (popmax 0.395%, nfe) (gnomAD).

What do computational predictors say about VCAN p.Val720Ala (c.2159T>C)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

VCAN p.Val720Ala

c.2159T>C · rs76418670 · VCV354403

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.395%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

vitreoretinal degeneration

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.018	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 -4.8	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.23 · regional, not allelic
Overall
CADD	0.001	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 0.395% European (non-Finnish) · 4,656/1,179,890 alleles

Filtering AF 0.385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.381%

Overall 0.313% 5,054/1,613,766 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.19%	31
European (non-Finnish)grpmax	0.395%	253
Remaining individualsnot grpmax-eligible	0.203%	492
Finnishnot grpmax-eligible	0.12%	830
Admixed American	0.113%	882
Ashkenazi Jewishnot grpmax-eligible	0.0845%	1,184
African / African-American	0.0747%	1,339
Middle Eastern	0.0495%	2,020
South Asian	0.0143%	7,005

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val720Ala
Coding: c.2159T>C
MANE Select: NM_004385
dbSNP: rs76418670
Type: single nucleotide variant
Location: chr5:83520465 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 720: 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.Val720Ile 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
VCAN p.Gly914Asp 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-val720ala (accessed [today's date]).

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