Is COL1A1 p.Ala559= (c.1677C>T) pathogenic?

COL1A1 p.Ala559= (c.1677C>T) is classified Likely benign in COL1A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-25). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with COL1A1 p.Ala559= (c.1677C>T)?

COL1A1 p.Ala559= (c.1677C>T) is associated with Cardiovascular phenotype, osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A1 p.Ala559= (c.1677C>T) in the general population?

COL1A1 p.Ala559= (c.1677C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

COL1A1 p.Ala559=

c.1677C>T · rs755073295 · VCV1158764

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.36	GERP -1.4, phastCons 0.44
Overall
CADD	10.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,856 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,613,782 alleles · very rare exomes 19/1,461,752 · genomes 1/152,030 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,428
South Asian	0.0022%	45,536
Admixed American	0.00167%	59,994
European (non-Finnish)	0.00127%	78,660

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.Ala559=
Coding: c.1677C>T
MANE Select: NM_000088
dbSNP: rs755073295
Type: single nucleotide variant
Location: chr17:50194033 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.26 · 14 PDB
Residue 559: the 'disordered' region; the 'triple-helical region' region

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.Ala559Thr Conflicting classifications of pathogenicity ★ ⚠ 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
COL1A1 c.1057-1G>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-ala559 (accessed [today's date]).

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