Is COL5A1 p.Pro855Arg (c.2564C>G) pathogenic?

COL5A1 p.Pro855Arg (c.2564C>G) is classified Conflicting classifications of pathogenicity in COL5A1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.2305); Rare (popmax 0.105%, amr); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A1 p.Pro855Arg (c.2564C>G)?

COL5A1 p.Pro855Arg (c.2564C>G) is associated with Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos syndrome, classic type, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A1 p.Pro855Arg (c.2564C>G) in the general population?

COL5A1 p.Pro855Arg (c.2564C>G) is rare (popmax 0.105%, amr) (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 COL5A1 p.Pro855Arg (c.2564C>G)?

AlphaMissense predicts likely benign (score 0.2305) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro855Arg

c.2564C>G · rs150539264 · VCV212950

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2305 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.2305	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 0.71, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 85 kb · p 6e-30 · regional, not allelic
Overall
CADD	23.5	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 0.105% Admixed American · 63/60,024 alleles

Filtering AF 0.0841% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0766%

Overall 0.0185% 299/1,613,342 alleles · rare exomes 210/1,461,042 · genomes 89/152,300 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.85%	35
Admixed Americangrpmax	0.105%	953
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0496%	2,016
African / African-American	0.044%	2,274
European (non-Finnish)	0.0119%	8,368

Amish 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.Pro855Arg
Coding: c.2564C>G
MANE Select: NM_000093
dbSNP: rs150539264
Type: single nucleotide variant
Location: chr9:134785068 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 855: the 'disordered' region; the 'triple-helical region' region

Full COL5A1 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: Ehlers-Danlos syndrome, classic type familial thoracic aortic aneurysm and aortic dissection

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL5A1 p.Pro855= Likely benign ★★ same residue
COL5A1 p.Pro855Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
COL5A1 p.Pro855His Likely benign ★ ⚠ 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

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-pro855arg (accessed [today's date]).

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