Is COL2A1 p.Val770Ile (c.2308G>A) pathogenic?

COL2A1 p.Val770Ile (c.2308G>A) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-07). AlphaMissense: likely benign (0.0621); Very rare (popmax 0.00891%, eas); Associated with Legg-Calve-Perthes disease.

What condition is associated with COL2A1 p.Val770Ile (c.2308G>A)?

COL2A1 p.Val770Ile (c.2308G>A) is associated with Legg-Calve-Perthes disease, Stickler syndrome type 1, multiple epiphyseal dysplasia, Beighton type (ClinVar).

How common is COL2A1 p.Val770Ile (c.2308G>A) in the general population?

COL2A1 p.Val770Ile (c.2308G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

How is Legg-Calvé-Perthes disease inherited?

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

What do computational predictors say about COL2A1 p.Val770Ile (c.2308G>A)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

COL2A1 p.Val770Ile

c.2308G>A · rs368583168 · VCV1418604

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Legg-Calve-Perthes disease

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.7, phastCons 0.93
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	17.88	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 0.00891% East Asian · 4/44,874 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00341% 55/1,613,832 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
Admixed American	0.005%	20,005
African / African-American	0.004%	25,003
European (non-Finnish)	0.00381%	26,218

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: COL2A1
Protein: p.Val770Ile
Coding: c.2308G>A
MANE Select: NM_001844
dbSNP: rs368583168
Type: single nucleotide variant
Location: chr12:47982154 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 770: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Legg-Calve-Perthes disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1 multiple epiphyseal dysplasia, Beighton type platyspondylic dysplasia, Torrance type Kniest dysplasia spondyloepiphyseal dysplasia congenita spondyloepimetaphyseal dysplasia, Strudwick type achondrogenesis type II spondyloperipheral dysplasia mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis spondyloepiphyseal dysplasia with metatarsal shortening Stickler syndrome, type I, nonsyndromic ocular spondyloepiphyseal dysplasia, Stanescu type vitreoretinopathy with phalangeal epiphyseal dysplasia avascular necrosis of femoral head, primary, 1

For Legg-Calvé-Perthes disease (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Childhood

Similar variants

COL2A1 p.Val770Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
COL2A1 c.1222-2A>G Pathogenic ★★ same condition
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1420-1G>A Pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+1G>A Likely pathogenic ★★ same condition
COL2A1 c.1581+1G>A Likely pathogenic ★★ 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/col2a1-p-val770ile (accessed [today's date]).

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