Is ACAN p.Pro68= (c.204A>C) pathogenic?

ACAN p.Pro68= (c.204A>C) is classified Benign in ACAN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-20). Common (popmax 5.73%, 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.

ACAN p.Pro68=

Q: What condition is associated with ACAN p.Pro68= (c.204A>C)?

ACAN p.Pro68= (c.204A>C) 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.Pro68= (c.204A>C) in the general population?

ACAN p.Pro68= (c.204A>C) is common (popmax 5.73%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.204A>C · rs372041880 · VCV790874

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.73%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

spondyloepiphyseal dysplasia, Kimberley type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3.5
Overall
CADD	5.607	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.73% South Asian · 5,216/91,070 alleles

Filtering AF 5.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.54%

Overall 0.351% 5,666/1,613,892 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	5.73%	17
Remaining individualsnot grpmax-eligible	0.482%	208
Middle Eastern	0.297%	337
East Asian	0.16%	623
African / African-American	0.0347%	2,884
Admixed American	0.005%	20,007
European (non-Finnish)	0.00254%	39,329

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.Pro68=
Coding: c.204A>C
MANE Select: NM_001369268
dbSNP: rs372041880
Type: single nucleotide variant
Location: chr15:88838796 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 68: a disulfide bond; an α-helix; 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

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.Pro68Gln 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
ACAN p.Glu254Ter Pathogenic ★★ same condition
ACAN p.Lys74Ter 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-pro68 (accessed [today's date]).

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