Is ACAN p.Ala248Pro (c.742G>C) pathogenic?

ACAN p.Ala248Pro (c.742G>C) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-31). AlphaMissense: likely pathogenic (0.9694); Absent from gnomAD v4.1.

How common is ACAN p.Ala248Pro (c.742G>C) in the general population?

ACAN p.Ala248Pro (c.742G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACAN p.Ala248Pro (c.742G>C)?

AlphaMissense predicts likely pathogenic (score 0.9694) — an in-silico prediction, not a clinical call.

ACAN p.Ala248Pro

c.742G>C · VCV3655133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9694 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9694	likely pathogenic · top 6% in ACAN
REVEL	0.445	indeterminate
SaProt	LLR -13.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACAN
Protein: p.Ala248Pro
Coding: c.742G>C
MANE Select: NM_001369268
Type: single nucleotide variant
Location: chr15:88841852 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 248: a β-strand; the link 1 domain

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

Similar variants

ACAN p.Ala248Thr Uncertain significance ★★ ⚠ same residue
ACAN p.Ala248= Benign ★★ 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-ala248pro (accessed [today's date]).

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