Is ACAN p.Arg502Pro (c.1505G>C) pathogenic?

ACAN p.Arg502Pro (c.1505G>C) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.6757); Ultra-rare (popmax 0.0863%, eas).

How common is ACAN p.Arg502Pro (c.1505G>C) in the general population?

ACAN p.Arg502Pro (c.1505G>C) is ultra-rare (popmax 0.0863%, eas) (gnomAD).

What do computational predictors say about ACAN p.Arg502Pro (c.1505G>C)?

AlphaMissense predicts likely pathogenic (score 0.6757) — an in-silico prediction, not a clinical call.

ACAN p.Arg502Pro

c.1505G>C · rs144835580 · VCV1374775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0863%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6757	likely pathogenic
REVEL	0.06	moderately benign-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	14.87	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 0.0863% East Asian · 37/42,856 alleles

Filtering AF 0.0643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0567%

Overall 0.0026% 41/1,577,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0863%	1,158
Remaining individualsnot grpmax-eligible	0.00654%	15,286

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.Arg502Pro
Coding: c.1505G>C
MANE Select: NM_001369268
dbSNP: rs144835580
Type: single nucleotide variant
Location: chr15:88847318 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 502: a disulfide bond; the link 3 domain; the 'g2-b' region

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

Similar variants

ACAN p.Arg502Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ACAN p.Arg502His Uncertain significance ★ ⚠ same residue
ACAN c.1733-2A>G Likely pathogenic ★★ same type
ACAN c.630-13G>A Pathogenic ★★ same type
ACAN c.7302+1G>A Pathogenic/Likely pathogenic ★★ same type
ACAN p.Arg236Ter Pathogenic ★★ same type
ACAN p.Arg386Ter Pathogenic/Likely pathogenic ★★ same type
ACAN p.Arg394Ter Pathogenic ★★ same type

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-arg502pro (accessed [today's date]).

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