Is ACAN p.Pro847Ala (c.2539C>G) pathogenic?

ACAN p.Pro847Ala (c.2539C>G) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-23). AlphaMissense: likely benign (0.0783); Very rare (popmax 0.00366%, nfe); Associated with spondyloepiphyseal dysplasia, Kimberley type.

How common is ACAN p.Pro847Ala (c.2539C>G) in the general population?

ACAN p.Pro847Ala (c.2539C>G) is very rare (popmax 0.00366%, nfe) (gnomAD).

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.Pro847Ala (c.2539C>G)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

ACAN p.Pro847Ala

Q: What condition is associated with ACAN p.Pro847Ala (c.2539C>G)?

ACAN p.Pro847Ala (c.2539C>G) 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).

c.2539C>G · rs372267862 · VCV1679571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00366%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepiphyseal dysplasia, Kimberley type

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -5.91	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 -0.89	GERP -3.3
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	0.768	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 0.00366% European (non-Finnish) · 43/1,176,444 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.00292% 47/1,607,296 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00483%	20,687
European (non-Finnish)grpmax	0.00366%	27,359
African / African-American	0.00134%	74,804

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro847Ala
Coding: c.2539C>G
MANE Select: NM_001369268
dbSNP: rs372267862
Type: single nucleotide variant
Location: chr15:88855124 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 847: the 'ks' region; the 'disordered' 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.Pro847= Likely benign ★ 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-pro847ala (accessed [today's date]).

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