Is COL1A1 p.Pro153Ala (c.457C>G) pathogenic?

COL1A1 p.Pro153Ala (c.457C>G) is classified Uncertain significance in COL1A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0621); Very rare (popmax 9.04e-05%, nfe); Associated with osteogenesis imperfecta type 1.

What condition is associated with COL1A1 p.Pro153Ala (c.457C>G)?

COL1A1 p.Pro153Ala (c.457C>G) is associated with osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A1 p.Pro153Ala (c.457C>G) in the general population?

COL1A1 p.Pro153Ala (c.457C>G) is very rare (popmax 9.04e-05%, nfe) (gnomAD).

What do computational predictors say about COL1A1 p.Pro153Ala (c.457C>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

COL1A1 p.Pro153Ala

c.457C>G · VCV3727192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.04e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

osteogenesis imperfecta type 1

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.5	indeterminate
SaProt	LLR -8.83	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 3.5	GERP -1.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 3,020 bp · p 0.063 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.04e-05% European (non-Finnish) · 1/1,105,994 alleles

Overall 6.82e-05% 1/1,467,176 alleles · very rare exomes 1/1,314,918 · genomes 0/152,258 · joint denominator

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: COL1A1
Protein: p.Pro153Ala
Coding: c.457C>G
MANE Select: NM_000088
Type: single nucleotide variant
Location: chr17:50199240 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.26 · 14 PDB
Residue 153: the 'disordered' region

Full COL1A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

COL1A1 p.Pro153= Likely benign ★★ same residue
COL1A1 p.Pro153Ser Uncertain significance ★ ⚠ same residue
COL1A1 p.Pro153fs Pathogenic ★ same residue
COL1A1 c.1003-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A1 c.103+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A1 c.103+2T>C Pathogenic ★★ same condition
COL1A1 c.104-1G>T Pathogenic/Likely pathogenic ★★ same condition
COL1A1 c.104-2A>G 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/col1a1-p-pro153ala (accessed [today's date]).

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