Is ACAN p.Pro753Leu (c.2258C>T) pathogenic?

ACAN p.Pro753Leu (c.2258C>T) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-28). AlphaMissense: likely benign (0.1594); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Pro753Leu (c.2258C>T)?

ACAN p.Pro753Leu (c.2258C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Pro753Leu (c.2258C>T) in the general population?

ACAN p.Pro753Leu (c.2258C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACAN p.Pro753Leu (c.2258C>T)?

AlphaMissense predicts likely benign (score 0.1594) — an in-silico prediction, not a clinical call.

ACAN p.Pro753Leu

c.2258C>T · rs749512612 · VCV1438309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1594 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1594	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.57	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 1.7	GERP -1.7, phastCons 0.003
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	12.18	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.0044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00112% 18/1,600,634 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,805
African / African-American	0.0094%	10,641
Finnishnot grpmax-eligible	0.00317%	31,579
Remaining individualsnot grpmax-eligible	0.00161%	62,066
South Asian	0.00113%	88,694
European (non-Finnish)	0.000256%	391,253

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.Pro753Leu
Coding: c.2258C>T
MANE Select: NM_001369268
dbSNP: rs749512612
Type: single nucleotide variant
Location: chr15:88852025 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 753: the 'ks' region; the 'disordered' 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.Pro753= Likely benign ★ 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-pro753leu (accessed [today's date]).

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