Is COL2A1 p.Ala181Ser (c.541G>T) pathogenic?

COL2A1 p.Ala181Ser (c.541G>T) is classified Benign in COL2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely benign (0.0825); Absent from gnomAD v4.1; Associated with spondyloepiphyseal dysplasia, Stanescu type.

What condition is associated with COL2A1 p.Ala181Ser (c.541G>T)?

COL2A1 p.Ala181Ser (c.541G>T) is associated with spondyloepiphyseal dysplasia, Stanescu type (ClinVar).

How common is COL2A1 p.Ala181Ser (c.541G>T) in the general population?

COL2A1 p.Ala181Ser (c.541G>T) is absent from gnomAD v4.1 (gnomAD).

How is Spondyloepiphyseal dysplasia, Stanescu type inherited?

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

What do computational predictors say about COL2A1 p.Ala181Ser (c.541G>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

COL2A1 p.Ala181Ser

c.541G>T · rs1939975439 · VCV983054

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spondyloepiphyseal dysplasia, Stanescu type

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -7.05	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 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	22.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL2A1
Protein: p.Ala181Ser
Coding: c.541G>T
MANE Select: NM_001844
dbSNP: rs1939975439
Type: single nucleotide variant
Location: chr12:47996616 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 181: a functional site (cleavage; by procollagen n-endopeptidase); the 'disordered' region

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

Disease context

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

For Spondyloepiphyseal dysplasia, Stanescu type (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

COL2A1 p.Ala181Val Likely pathogenic ★ ⚠ same residue
COL2A1 p.Ala302Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
COL2A1 p.Arg565Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Arg653Ter Pathogenic ★★ same condition
COL2A1 p.Arg989Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Cys86Ter Pathogenic ★★ same condition
COL2A1 p.Gly1041Ser Pathogenic ★★ same condition
COL2A1 p.Gly1086Arg 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-ala181ser (accessed [today's date]).

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