Is COL1A1 p.Pro57Ser (c.169C>T) pathogenic?

COL1A1 p.Pro57Ser (c.169C>T) is classified Uncertain significance in COL1A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.1628); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with COL1A1 p.Pro57Ser (c.169C>T)?

COL1A1 p.Pro57Ser (c.169C>T) is associated with Cardiovascular phenotype, osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A1 p.Pro57Ser (c.169C>T) in the general population?

COL1A1 p.Pro57Ser (c.169C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COL1A1 p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.1628) — an in-silico prediction, not a clinical call.

COL1A1 p.Pro57Ser

c.169C>T · rs773571012 · VCV2088665

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1628	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.17	GERP -2.2
Regional constraint	o/e 0.88	unconstrained · MANE · 3,020 bp · p 0.063 · regional, not allelic
Overall
CADD	19.24	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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 6.2e-05% 1/1,614,068 alleles · very rare exomes 0/1,461,872 · genomes 1/152,196 · 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.Pro57Ser
Coding: c.169C>T
MANE Select: NM_000088
dbSNP: rs773571012
Type: single nucleotide variant
Location: chr17:50199882 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.26 · 14 PDB
Residue 57: the vwfc domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteogenesis imperfecta type 1

Similar variants

COL1A1 p.Pro57Ala Likely benign ★ same residue
COL1A1 p.Pro57Thr Likely benign ★ ⚠ 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
COL1A1 c.1056+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/col1a1-p-pro57ser (accessed [today's date]).

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