Is COL2A1 p.Asp1418= (c.4254C>T) pathogenic?

COL2A1 p.Asp1418= (c.4254C>T) is classified Likely benign in COL2A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-15). Very rare (popmax 0.0022%, sas); Associated with achondrogenesis type II.

What condition is associated with COL2A1 p.Asp1418= (c.4254C>T)?

COL2A1 p.Asp1418= (c.4254C>T) is associated with achondrogenesis type II, Stickler syndrome type 1, multiple epiphyseal dysplasia, Beighton type (ClinVar).

How common is COL2A1 p.Asp1418= (c.4254C>T) in the general population?

COL2A1 p.Asp1418= (c.4254C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Achondrogenesis inherited?

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

COL2A1 p.Asp1418=

c.4254C>T · rs748658390 · VCV1135907

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

achondrogenesis type II

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 -3.6	GERP -3.8
Overall
CADD	3.962	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000682% 11/1,614,074 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asiangrpmax	0.0022%	45,545
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000593%	168,576

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp1418=
Coding: c.4254C>T
MANE Select: NM_001844
dbSNP: rs748658390
Type: single nucleotide variant
Location: chr12:47974152 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1418: the fibrillar collagen nc1 domain; a disulfide bond

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

Disease context

achondrogenesis type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1 multiple epiphyseal dysplasia, Beighton type Legg-Calve-Perthes disease platyspondylic dysplasia, Torrance type Kniest dysplasia spondyloepiphyseal dysplasia congenita spondyloepimetaphyseal dysplasia, Strudwick type spondylometaphyseal dysplasia, 'corner fracture' type 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 Achondrogenesis (Orphanet):

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

Similar variants

COL2A1 p.Asp1418Glu Uncertain significance ★ ⚠ 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-asp1418 (accessed [today's date]).

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