Is COL1A2 p.Pro552Ser (c.1654C>T) pathogenic?

COL1A2 p.Pro552Ser (c.1654C>T) is classified Conflicting classifications of pathogenicity in COL1A2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0618); Rare (popmax 0.132%, mid); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL1A2 p.Pro552Ser (c.1654C>T)?

COL1A2 p.Pro552Ser (c.1654C>T) is associated with Ehlers-Danlos syndrome, classic type, 1, osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A2 p.Pro552Ser (c.1654C>T) in the general population?

COL1A2 p.Pro552Ser (c.1654C>T) is rare (popmax 0.132%, mid) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about COL1A2 p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

COL1A2 p.Pro552Ser

c.1654C>T · rs763695362 · VCV393240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -7.59	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 2.5e-23 · regional, not allelic
Overall
CADD	23.3	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 0.132% Middle Eastern · 8/6,078 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.0044% 71/1,613,338 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	760
South Asian	0.0143%	7,003
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)	0.00356%	28,087
African / African-American	0.00134%	74,770

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: COL1A2
Protein: p.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_000089
dbSNP: rs763695362
Type: single nucleotide variant
Location: chr7:94413936 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 552: the 'disordered' region

Full COL1A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, classic type, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteogenesis imperfecta type 1

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL1A2 c.1197+5G>A Pathogenic ★★ same condition
COL1A2 c.1503+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.1503+1G>C Pathogenic ★★ same condition
COL1A2 c.1557+3A>G Pathogenic ★★ same condition
COL1A2 c.2026-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.2133+6T>A Pathogenic ★★ same condition
COL1A2 c.226-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.2295+1G>A 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/col1a2-p-pro552ser (accessed [today's date]).

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