Is ACAN p.Lys80Arg (c.239A>G) pathogenic?

ACAN p.Lys80Arg (c.239A>G) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1168); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Lys80Arg (c.239A>G)?

ACAN p.Lys80Arg (c.239A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Lys80Arg (c.239A>G) in the general population?

ACAN p.Lys80Arg (c.239A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACAN p.Lys80Arg (c.239A>G)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

ACAN p.Lys80Arg

c.239A>G · rs972979581 · VCV1922409

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -3.86	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 6.2	GERP -0.46, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	22.6	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000929% 15/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
African / African-American	0.00134%	74,906
European (non-Finnish)	0.0011%	90,761

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.Lys80Arg
Coding: c.239A>G
MANE Select: NM_001369268
dbSNP: rs972979581
Type: single nucleotide variant
Location: chr15:88838831 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 80: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACAN p.Lys80Gln Uncertain significance ★ ⚠ same residue
ACAN p.Leu1606Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Ala1404Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2105Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2163Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2191Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2278Asp Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2409Gly 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-lys80arg (accessed [today's date]).

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