Is COL5A1 p.Pro1296= (c.3888G>A) pathogenic?

COL5A1 p.Pro1296= (c.3888G>A) is classified Benign/Likely benign in COL5A1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-07). Ultra-rare (popmax 0.0575%, afr); Associated with fibromuscular dysplasia, multifocal.

What condition is associated with COL5A1 p.Pro1296= (c.3888G>A)?

COL5A1 p.Pro1296= (c.3888G>A) is associated with fibromuscular dysplasia, multifocal, Ehlers-Danlos syndrome, classic type, 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A1 p.Pro1296= (c.3888G>A) in the general population?

COL5A1 p.Pro1296= (c.3888G>A) is ultra-rare (popmax 0.0575%, afr) (gnomAD).

COL5A1 p.Pro1296=

c.3888G>A · rs375631252 · VCV136883

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0575%, afr)

Conditions

fibromuscular dysplasia, multifocal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Overall
CADD	0.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0575% African / African-American · 42/73,070 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0388%

Overall 0.00858% 133/1,550,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.157%	637
African / African-Americangrpmax	0.0575%	1,740
Remaining individualsnot grpmax-eligible	0.0283%	3,535
Middle Eastern	0.0166%	6,014
Admixed American	0.00392%	25,504
East Asian	0.00244%	40,946
South Asian	0.00238%	42,028
European (non-Finnish)	0.00201%	49,871

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL5A1
Protein: p.Pro1296=
Coding: c.3888G>A
MANE Select: NM_000093
dbSNP: rs375631252
Type: single nucleotide variant
Location: chr9:134814018 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 1296: the 'disordered' region; the 'triple-helical region' region

Full COL5A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fibromuscular dysplasia, multifocal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, classic type, 1 familial thoracic aortic aneurysm and aortic dissection Ehlers-Danlos syndrome

Similar variants

COL5A1 p.Pro1296Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL5A1 c.1332+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.1720-11T>A Likely pathogenic ★★ same condition
COL5A1 c.2034+1G>A Pathogenic ★★ same condition
COL5A1 c.2430+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.2430+1G>C Pathogenic ★★ same condition
COL5A1 c.2701-25T>G Pathogenic ★★ same condition
COL5A1 c.4338+1G>A 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/col5a1-p-pro1296 (accessed [today's date]).

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