Is ACAN p.Ala63Asp (c.188C>A) pathogenic?

ACAN p.Ala63Asp (c.188C>A) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5487); Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, aggrecan type.

What condition is associated with ACAN p.Ala63Asp (c.188C>A)?

ACAN p.Ala63Asp (c.188C>A) is associated with spondyloepimetaphyseal dysplasia, aggrecan type (ClinVar).

How common is ACAN p.Ala63Asp (c.188C>A) in the general population?

ACAN p.Ala63Asp (c.188C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACAN p.Ala63Asp (c.188C>A)?

AlphaMissense predicts ambiguous (score 0.5487) — an in-silico prediction, not a clinical call.

ACAN p.Ala63Asp

Q: How is Spondyloepimetaphyseal dysplasia, aggrecan type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.188C>A · rs1245147885 · VCV2584787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5487 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

spondyloepimetaphyseal dysplasia, aggrecan type

Computational evidence

Protein change
AlphaMissense	0.5487	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACAN
Protein: p.Ala63Asp
Coding: c.188C>A
MANE Select: NM_001369268
dbSNP: rs1245147885
Type: single nucleotide variant
Location: chr15:88838780 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 63: a disulfide bond; the ig-like v-type domain; the 'g1-a' region

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

Disease context

spondyloepimetaphyseal dysplasia, aggrecan type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia, aggrecan type (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACAN p.Ala63Pro Uncertain significance ★ ⚠ same residue
ACAN p.Ala63Thr Uncertain significance ★ ⚠ same residue
ACAN p.Arg675Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Asp2419Asn Likely pathogenic ★★ same condition
ACAN p.Tyr164Ter Pathogenic ★★ same condition
ACAN p.Ala171Val Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2503Gln Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2560Trp 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-ala63asp (accessed [today's date]).

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