Is ACAN p.Ser997Pro (c.2989T>C) pathogenic?

ACAN p.Ser997Pro (c.2989T>C) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: ambiguous (0.49); No allele count reported in gnomAD v4.1 (AN 631,720); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Ser997Pro (c.2989T>C)?

ACAN p.Ser997Pro (c.2989T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Ser997Pro (c.2989T>C) in the general population?

ACAN p.Ser997Pro (c.2989T>C) is no allele count reported in gnomAD v4.1 (AN 631,720) (gnomAD).

What do computational predictors say about ACAN p.Ser997Pro (c.2989T>C)?

AlphaMissense predicts ambiguous (score 0.49) — an in-silico prediction, not a clinical call.

ACAN p.Ser997Pro

c.2989T>C · VCV3466550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.49 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 631,720)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.49	ambiguous
REVEL	0.574	indeterminate
SaProt	LLR -11.82	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP 0.58, phastCons 0.22
Regional constraint	o/e 0.38	unconstrained · MANE · 1,434 bp · p 4e-11 · regional, not allelic
Overall
CADD	23.2	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

No allele count reported in gnomAD v4.1 (AN 631,720). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACAN
Protein: p.Ser997Pro
Coding: c.2989T>C
MANE Select: NM_001369268
Type: single nucleotide variant
Location: chr15:88855574 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 997: the 'cs-1' region; the '35 x 19 aa approximate tandem repeats of e-[ivdg]-[lv]-[ev]-[gti]-[sta]-[atv]-[sp]-[ga]-[vifad]-[gedl]-[de]-[lvi]-[sg]-[gerk]-[lv]-p-s-g' 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.Ser997Phe Uncertain significance ★ ⚠ same residue
ACAN p.Ser997Thr Uncertain significance ★ ⚠ same residue
ACAN p.Ser997Tyr 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

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-ser997pro (accessed [today's date]).

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