Is VCAN p.Phe1035Val (c.3103T>G) pathogenic?

VCAN p.Phe1035Val (c.3103T>G) is classified Uncertain significance in VCAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-28). AlphaMissense: likely benign (0.1192); Very rare (popmax 8.47e-05%, nfe); Associated with vitreoretinal degeneration.

What condition is associated with VCAN p.Phe1035Val (c.3103T>G)?

VCAN p.Phe1035Val (c.3103T>G) is associated with vitreoretinal degeneration (ClinVar).

How common is VCAN p.Phe1035Val (c.3103T>G) in the general population?

VCAN p.Phe1035Val (c.3103T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about VCAN p.Phe1035Val (c.3103T>G)?

AlphaMissense predicts likely benign (score 0.1192) — an in-silico prediction, not a clinical call.

VCAN p.Phe1035Val

c.3103T>G · rs886060821 · VCV354413

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

vitreoretinal degeneration

Computational evidence

Protein change
AlphaMissense	0.1192	likely benign
REVEL	0.16	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 0.19	GERP 0.34, phastCons 0.13
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.23 · regional, not allelic
Overall
CADD	7.502	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 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.2e-05% 1/1,614,126 alleles · very rare exomes 1/1,461,814 · genomes 0/152,312 · 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.Phe1035Val
Coding: c.3103T>G
MANE Select: NM_004385
dbSNP: rs886060821
Type: single nucleotide variant
Location: chr5:83521409 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 1035: 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 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
VCAN p.His1946Tyr 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-phe1035val (accessed [today's date]).

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