Is COL5A2 p.Leu17Ser (c.50T>C) pathogenic?

COL5A2 p.Leu17Ser (c.50T>C) is classified Uncertain significance in COL5A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely benign (0.2423); Very rare (popmax 0.00133%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with COL5A2 p.Leu17Ser (c.50T>C)?

COL5A2 p.Leu17Ser (c.50T>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A2 p.Leu17Ser (c.50T>C) in the general population?

COL5A2 p.Leu17Ser (c.50T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about COL5A2 p.Leu17Ser (c.50T>C)?

AlphaMissense predicts likely benign (score 0.2423) — an in-silico prediction, not a clinical call.

COL5A2 p.Leu17Ser

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.50T>C · VCV4842229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.2423	likely benign
REVEL	0.377	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 146 kb · p 1.2e-16 · regional, not allelic
Overall
CADD	21.9	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 0.00133% African / African-American · 1/74,984 alleles

Overall 0.000124% 2/1,611,136 alleles · very rare exomes 2/1,458,900 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,984
European (non-Finnish)	8.49e-05%	1,178,498

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: COL5A2
Protein: p.Leu17Ser
Coding: c.50T>C
MANE Select: NM_000393
Type: single nucleotide variant
Location: chr2:189179555 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15

Full COL5A2 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

COL5A2 c.1005+4T>C Uncertain significance ★★ same condition
COL5A2 c.1618-7G>A Uncertain significance ★★ same condition
COL5A2 c.2031+3A>G Uncertain significance ★★ same condition
COL5A2 c.798+5G>A Uncertain significance ★★ same condition
COL5A2 p.Ala1076Val Uncertain significance ★★ ⚠ same condition
COL5A2 p.Ala1323Thr Uncertain significance ★★ ⚠ same condition
COL5A2 p.Ala196Pro Uncertain significance ★★ ⚠ same condition
COL5A2 p.Ala592Thr Uncertain significance ★★ ⚠ 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/col5a2-p-leu17ser (accessed [today's date]).

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