Is COL5A1 p.Pro705Arg (c.2114C>G) pathogenic?

COL5A1 p.Pro705Arg (c.2114C>G) is classified Uncertain significance in COL5A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-26). AlphaMissense: likely benign (0.3052); Very rare (popmax 0.00133%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with COL5A1 p.Pro705Arg (c.2114C>G)?

COL5A1 p.Pro705Arg (c.2114C>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A1 p.Pro705Arg (c.2114C>G) in the general population?

COL5A1 p.Pro705Arg (c.2114C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about COL5A1 p.Pro705Arg (c.2114C>G)?

AlphaMissense predicts likely benign (score 0.3052) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro705Arg

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2114C>G · VCV4869254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.3052	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.5, phastCons 0.16
Regional constraint	o/e 0.71	unconstrained · MANE · 85 kb · p 6e-30 · regional, not allelic
Overall
CADD	21.0	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 0.00133% African / African-American · 1/74,936 alleles

Overall 0.000124% 2/1,614,046 alleles · very rare exomes 1/1,461,842 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,936
South Asian	0.0011%	91,078

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.Pro705Arg
Coding: c.2114C>G
MANE Select: NM_000093
Type: single nucleotide variant
Location: chr9:134766479 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 705: the 'disordered' region; the 'triple-helical region' region; a modified residue (hydroxyproline)

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

COL5A1 p.Pro705Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL5A1 p.Pro705= Likely benign ★ same residue
COL5A1 c.1720-11T>A Likely pathogenic ★★ same condition
COL5A1 c.655-1G>C Likely pathogenic ★★ same condition
COL5A1 c.655-2A>T Likely pathogenic ★★ same condition
COL5A1 p.Arg1062Ter Pathogenic ★★ same condition
COL5A1 p.Arg594Ter Pathogenic/Likely pathogenic ★★ same condition
COL5A1 p.Arg912Ter 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-pro705arg (accessed [today's date]).

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