Is ACAN p.Glu249Asp (c.747G>C) pathogenic?

ACAN p.Glu249Asp (c.747G>C) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-02). AlphaMissense: ambiguous (0.513); Very rare (popmax 0.00335%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Glu249Asp (c.747G>C)?

ACAN p.Glu249Asp (c.747G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Glu249Asp (c.747G>C) in the general population?

ACAN p.Glu249Asp (c.747G>C) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about ACAN p.Glu249Asp (c.747G>C)?

AlphaMissense predicts ambiguous (score 0.513) — an in-silico prediction, not a clinical call.

ACAN p.Glu249Asp

c.747G>C · rs768804104 · VCV1418361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.513	ambiguous
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	21.7	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 0.00335% Admixed American · 2/59,728 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000186% 3/1,612,346 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,864
European (non-Finnish)	8.48e-05%	1,179,454

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.Glu249Asp
Coding: c.747G>C
MANE Select: NM_001369268
dbSNP: rs768804104
Type: single nucleotide variant
Location: chr15:88841857 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB

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.Glu249Lys Conflicting classifications of pathogenicity ★ ⚠ 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-glu249asp (accessed [today's date]).

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