Is ACAN p.Pro338Arg (c.1013C>G) pathogenic?

ACAN p.Pro338Arg (c.1013C>G) is classified Uncertain significance in ACAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely pathogenic (0.9234); Very rare (popmax 0.00402%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Pro338Arg (c.1013C>G)?

ACAN p.Pro338Arg (c.1013C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Pro338Arg (c.1013C>G) in the general population?

ACAN p.Pro338Arg (c.1013C>G) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about ACAN p.Pro338Arg (c.1013C>G)?

AlphaMissense predicts likely pathogenic (score 0.9234) — an in-silico prediction, not a clinical call.

ACAN p.Pro338Arg

c.1013C>G · VCV3469189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9234	likely pathogenic · top 10% in ACAN
REVEL	0.252	benign-leaning
SaProt	LLR -15.66	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.24, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	23.3	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 0.00402% African / African-American · 3/74,608 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000188% 3/1,595,820 alleles · very rare

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.Pro338Arg
Coding: c.1013C>G
MANE Select: NM_001369268
Type: single nucleotide variant
Location: chr15:88843610 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 338: 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.Pro338Leu Uncertain significance ★★ ⚠ same residue
ACAN p.Pro338Ala Uncertain significance ★★ ⚠ same residue
ACAN p.Pro338= 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

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-pro338arg (accessed [today's date]).

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