Is ACAN p.Val462Ile (c.1384G>A) pathogenic?

ACAN p.Val462Ile (c.1384G>A) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-12). AlphaMissense: likely benign (0.1446); Ultra-rare (popmax 0.0121%, eas); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Val462Ile (c.1384G>A)?

ACAN p.Val462Ile (c.1384G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Val462Ile (c.1384G>A) in the general population?

ACAN p.Val462Ile (c.1384G>A) is ultra-rare (popmax 0.0121%, eas) (gnomAD).

What do computational predictors say about ACAN p.Val462Ile (c.1384G>A)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

ACAN p.Val462Ile

c.1384G>A · rs200734577 · VCV3011914

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	18.89	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% East Asian · 5/41,214 alleles

Filtering AF 0.00476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00307%

Overall 0.00119% 16/1,342,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0121%	8,243
South Asian	0.00274%	36,445
African / African-American	0.0014%	71,620
European (non-Finnish)	0.000715%	139,917

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: ACAN
Protein: p.Val462Ile
Coding: c.1384G>A
MANE Select: NM_001369268
dbSNP: rs200734577
Type: single nucleotide variant
Location: chr15:88845837 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACAN p.Val462Phe Uncertain significance ★★ ⚠ same residue
ACAN p.Val462= Likely benign ★★ same residue
ACAN p.Leu1606Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Ala1404Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2105Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2163Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2191Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2278Asp 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/acan-p-val462ile (accessed [today's date]).

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