Is COL2A1 p.Ala778= (c.2334C>T) pathogenic?

COL2A1 p.Ala778= (c.2334C>T) is classified Benign/Likely benign in COL2A1 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-04-01). Rare (popmax 0.61%, nfe); Associated with spondyloepiphyseal dysplasia congenita.

What condition is associated with COL2A1 p.Ala778= (c.2334C>T)?

COL2A1 p.Ala778= (c.2334C>T) is associated with spondyloepiphyseal dysplasia congenita, connective tissue disorder, Stickler syndrome type 1 (ClinVar).

How common is COL2A1 p.Ala778= (c.2334C>T) in the general population?

COL2A1 p.Ala778= (c.2334C>T) is rare (popmax 0.61%, nfe) (gnomAD).

How is Spondyloepiphyseal dysplasia congenita inherited?

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

COL2A1 p.Ala778=

c.2334C>T · rs35504014 · VCV166926

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

rare (popmax 0.61%, nfe)

Conditions

spondyloepiphyseal dysplasia congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -0.37, phastCons 0.022
Overall
CADD	8.064	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.61% European (non-Finnish) · 7,193/1,179,910 alleles

Filtering AF 0.598% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.593%

Overall 0.48% 7,752/1,613,962 alleles · rare exomes 7,347/1,461,766 · genomes 405/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.61%	164
Remaining individualsnot grpmax-eligible	0.328%	305
Finnishnot grpmax-eligible	0.319%	314
Admixed American	0.0933%	1,071
African / African-American	0.088%	1,137
South Asian	0.0296%	3,373
Middle Eastern	0.0165%	6,062

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.Ala778=
Coding: c.2334C>T
MANE Select: NM_001844
dbSNP: rs35504014
Type: single nucleotide variant
Location: chr12:47982128 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 778: the 'disordered' region; the 'triple-helical region' region

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

Disease context

spondyloepiphyseal dysplasia congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: connective tissue disorder Stickler syndrome type 1 multiple epiphyseal dysplasia, Beighton type Legg-Calve-Perthes disease platyspondylic dysplasia, Torrance type Kniest dysplasia spondyloepimetaphyseal dysplasia, Strudwick type spondylometaphyseal dysplasia, 'corner fracture' 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 type 2 collagenopathy vitreoretinopathy with phalangeal epiphyseal dysplasia avascular necrosis of femoral head, primary, 1

For Spondyloepiphyseal dysplasia congenita (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

COL2A1 p.Ala778Val Likely benign ★ 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-ala778 (accessed [today's date]).

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