Is COL2A1 p.Pro49= (c.147G>A) pathogenic?

COL2A1 p.Pro49= (c.147G>A) is classified Benign/Likely benign in COL2A1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-18). Ultra-rare (popmax 0.0802%, eas); Associated with Stickler syndrome type 1.

What condition is associated with COL2A1 p.Pro49= (c.147G>A)?

COL2A1 p.Pro49= (c.147G>A) is associated with Stickler syndrome type 1 (ClinVar).

How common is COL2A1 p.Pro49= (c.147G>A) in the general population?

COL2A1 p.Pro49= (c.147G>A) is ultra-rare (popmax 0.0802%, eas) (gnomAD).

How is Stickler syndrome inherited?

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

COL2A1 p.Pro49=

c.147G>A · rs372734539 · VCV1137831

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, eas)

Conditions

Stickler syndrome type 1

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 -1.2	GERP -3.8
Overall
CADD	9.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0802% East Asian · 36/44,880 alleles

Filtering AF 0.0595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00459% 74/1,613,894 alleles · ultra-rare exomes 63/1,461,714 · genomes 11/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0802%	1,247
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.00267%	37,480
European (non-Finnish)	0.00229%	43,704
South Asian	0.0022%	45,532
Admixed American	0.00167%	60,020

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.Pro49=
Coding: c.147G>A
MANE Select: NM_001844
dbSNP: rs372734539
Type: single nucleotide variant
Location: chr12:48000064 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 49: a β-strand; the vwfc domain

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

Disease context

Stickler syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Stickler syndrome (Orphanet):

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

Similar variants

COL2A1 p.Pro49Leu 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.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1833+1G>A Pathogenic ★★ same condition
COL2A1 c.1887+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1888-2A>C 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-pro49 (accessed [today's date]).

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