Is ACAN p.Arg274Trp (c.820C>T) pathogenic?

ACAN p.Arg274Trp (c.820C>T) is classified Conflicting classifications of pathogenicity in ACAN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-21). AlphaMissense: ambiguous (0.4078); Rare (popmax 0.162%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Arg274Trp (c.820C>T)?

ACAN p.Arg274Trp (c.820C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Arg274Trp (c.820C>T) in the general population?

ACAN p.Arg274Trp (c.820C>T) is rare (popmax 0.162%, sas) (gnomAD).

What do computational predictors say about ACAN p.Arg274Trp (c.820C>T)?

AlphaMissense predicts ambiguous (score 0.4078) — an in-silico prediction, not a clinical call.

ACAN p.Arg274Trp

c.820C>T · rs369870175 · VCV2172005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4078 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.162%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4078	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -9.49	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 3.3	GERP -1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	24.7	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 0.162% South Asian · 147/90,634 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.0192% 308/1,604,432 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.162%	617
Middle Eastern	0.116%	863
Remaining individualsnot grpmax-eligible	0.0226%	4,425
European (non-Finnish)	0.011%	9,093
Admixed American	0.0101%	9,942
African / African-American	0.00668%	14,962

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.Arg274Trp
Coding: c.820C>T
MANE Select: NM_001369268
dbSNP: rs369870175
Type: single nucleotide variant
Location: chr15:88843417 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 274: a disulfide bond; an α-helix; the link 2 domain; the 'g1-b'' 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.Arg274Gln 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
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-arg274trp (accessed [today's date]).

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