Is COL9A2 p.Val581Ile (c.1741G>A) pathogenic?

COL9A2 p.Val581Ile (c.1741G>A) is classified Benign/Likely benign in COL9A2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.0523); Common (popmax 17.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with epiphyseal dysplasia, multiple, 2.

What condition is associated with COL9A2 p.Val581Ile (c.1741G>A)?

COL9A2 p.Val581Ile (c.1741G>A) is associated with epiphyseal dysplasia, multiple, 2 (ClinVar).

What do computational predictors say about COL9A2 p.Val581Ile (c.1741G>A)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

COL9A2 p.Val581Ile

Q: How common is COL9A2 p.Val581Ile (c.1741G>A) in the general population?

COL9A2 p.Val581Ile (c.1741G>A) is common (popmax 17.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Multiple epiphyseal dysplasia due to collagen 9 anomaly inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1741G>A · rs3737821 · VCV196620

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 17.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epiphyseal dysplasia, multiple, 2

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.67	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 -0.32	GERP -0.44
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	10.33	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 17.3% African / African-American · 12,907/74,582 alleles

Filtering AF 17.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 17%

Overall 2.94% 47,080/1,600,116 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	17.3%	6
Admixed American	5.26%	19
Ashkenazi Jewishnot grpmax-eligible	4.08%	24
South Asian	3.52%	28
Remaining individualsnot grpmax-eligible	3.26%	31
East Asian	3.2%	31
Finnishnot grpmax-eligible	2.44%	41
Middle Eastern	2.36%	42
European (non-Finnish)	1.85%	54
Amishnot grpmax-eligible	0.11%	910

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: COL9A2
Protein: p.Val581Ile
Coding: c.1741G>A
MANE Select: NM_001852
dbSNP: rs3737821
Type: single nucleotide variant
Location: chr1:40302672 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 581: a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in); the 'triple-helical region 2 (col2)' region; the 'disordered' region

Full COL9A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epiphyseal dysplasia, multiple, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple epiphyseal dysplasia due to collagen 9 anomaly (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

COL9A2 c.186+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL9A2 c.*67A>G Uncertain significance ★★ same condition
COL9A2 p.Arg136Gln Uncertain significance ★★ ⚠ same condition
COL9A2 p.Arg375Leu Uncertain significance ★★ ⚠ same condition
COL9A2 p.Asp428His Uncertain significance ★★ ⚠ same condition
COL9A2 p.Asp519His Uncertain significance ★★ ⚠ same condition
COL9A2 p.Gly250Ala Uncertain significance ★★ ⚠ same condition
COL9A2 p.Gly274Ser 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/col9a2-p-val581ile (accessed [today's date]).

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