Is ACAN p.Arg585Ser (c.1753C>A) pathogenic?

ACAN p.Arg585Ser (c.1753C>A) is classified Benign in ACAN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.3587); Common (popmax 9.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with spondyloepiphyseal dysplasia, Kimberley type.

How is Spondyloepiphyseal dysplasia, Kimberley type inherited?

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

What do computational predictors say about ACAN p.Arg585Ser (c.1753C>A)?

AlphaMissense predicts ambiguous (score 0.3587) — an in-silico prediction, not a clinical call.

ACAN p.Arg585Ser

Q: What condition is associated with ACAN p.Arg585Ser (c.1753C>A)?

ACAN p.Arg585Ser (c.1753C>A) is associated with spondyloepiphyseal dysplasia, Kimberley type, spondyloepimetaphyseal dysplasia, aggrecan type, short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (ClinVar).

Q: How common is ACAN p.Arg585Ser (c.1753C>A) in the general population?

ACAN p.Arg585Ser (c.1753C>A) is common (popmax 9.8%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1753C>A · rs144501729 · VCV1206136

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3587 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.8%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

spondyloepiphyseal dysplasia, Kimberley type

Computational evidence

Protein change
AlphaMissense	0.3587	ambiguous
REVEL	0.084	moderately benign-leaning
SaProt	LLR -3.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP 0.85, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	19.21	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

Grpmax group 9.8% South Asian · 8,764/89,452 alleles

Filtering AF 9.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.56%

Overall 0.62% 9,898/1,596,588 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	9.8%	10
Remaining individualsnot grpmax-eligible	0.893%	112
East Asian	0.739%	135
Middle Eastern	0.327%	306
Admixed American	0.0456%	2,195
African / African-American	0.0321%	3,112
European (non-Finnish)	0.0156%	6,420
Finnishnot grpmax-eligible	0.00635%	15,743

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.Arg585Ser
Coding: c.1753C>A
MANE Select: NM_001369268
dbSNP: rs144501729
Type: single nucleotide variant
Location: chr15:88849458 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 585: the 'g2-b'' region; the link 4 domain

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

Disease context

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

Also linked: spondyloepimetaphyseal dysplasia, aggrecan type short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

For Spondyloepiphyseal dysplasia, Kimberley type (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ACAN p.Arg585His Uncertain significance ★★ ⚠ same residue
ACAN p.Arg585= Likely benign ★★ same residue
ACAN p.Arg585Cys Uncertain significance ★ ⚠ same residue
ACAN c.1733-2A>G Likely pathogenic ★★ same condition
ACAN c.7302+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Arg236Ter Pathogenic ★★ same condition
ACAN p.Arg675Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Asp2419Asn Likely pathogenic ★★ 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-arg585ser (accessed [today's date]).

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