Is ACAN p.Cys246Arg (c.736T>C) pathogenic?

ACAN p.Cys246Arg (c.736T>C) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-16). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1.

How common is ACAN p.Cys246Arg (c.736T>C) in the general population?

ACAN p.Cys246Arg (c.736T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACAN p.Cys246Arg (c.736T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

ACAN p.Cys246Arg

c.736T>C · VCV3640216

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 1% in ACAN
REVEL	0.699	pathogenic-leaning
SaProt	LLR -16.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	26.3	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.Cys246Arg
Coding: c.736T>C
MANE Select: NM_001369268
Type: single nucleotide variant
Location: chr15:88841846 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 246: a disulfide bond; a β-strand; the link 1 domain; the 'g1-b' region

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

Similar variants

ACAN p.Cys246Gly Uncertain significance ★ ⚠ 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
ACAN p.Arg675Ter Pathogenic/Likely 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-cys246arg (accessed [today's date]).

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