Is COL2A1 p.Thr9Ser (c.25A>T) pathogenic?

COL2A1 p.Thr9Ser (c.25A>T) is classified Benign in COL2A1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-08). AlphaMissense: likely benign (0.0845); Common (popmax 84.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with type 2 collagenopathy.

What condition is associated with COL2A1 p.Thr9Ser (c.25A>T)?

COL2A1 p.Thr9Ser (c.25A>T) is associated with type 2 collagenopathy, Stickler syndrome type 1 (ClinVar).

What do computational predictors say about COL2A1 p.Thr9Ser (c.25A>T)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

COL2A1 p.Thr9Ser

Q: How common is COL2A1 p.Thr9Ser (c.25A>T) in the general population?

COL2A1 p.Thr9Ser (c.25A>T) is common (popmax 84.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.25A>T · rs3803183 · VCV93788

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 84.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 collagenopathy

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -5.91	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 3.8	GERP 0.18, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	18.75	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 84.3% European (non-Finnish) · 965,729/1,145,632 alleles

Filtering AF 84.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.1%

Overall 80.9% 1,253,225/1,549,070 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	84.3%	1
Middle Eastern	83%	1
Ashkenazi Jewishnot grpmax-eligible	79.6%	1
Remaining individualsnot grpmax-eligible	79.5%	1
South Asian	76.4%	1
Amishnot grpmax-eligible	75.7%	1
Finnishnot grpmax-eligible	75.7%	1
African / African-American	66.1%	2
Admixed American	60.3%	2
East Asian	57.3%	2

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.Thr9Ser
Coding: c.25A>T
MANE Select: NM_001844
dbSNP: rs3803183
Type: single nucleotide variant
Location: chr12:48004297 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 9: a UniProt-annotated variant site (in)

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

Disease context

type 2 collagenopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1

Similar variants

COL2A1 p.Thr9Arg Uncertain significance ★ ⚠ same residue
COL2A1 c.1222-2A>G Pathogenic ★★ same condition
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1581+1G>A Likely pathogenic ★★ same condition
COL2A1 c.1833+1G>A Pathogenic ★★ same condition
COL2A1 c.1887+1G>A Pathogenic/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-thr9ser (accessed [today's date]).

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