Is COL5A1 p.Pro136Ser (c.406C>T) pathogenic?

COL5A1 p.Pro136Ser (c.406C>T) is classified Conflicting classifications of pathogenicity in COL5A1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.8106); Very rare (popmax 0.00593%, nfe); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A1 p.Pro136Ser (c.406C>T)?

COL5A1 p.Pro136Ser (c.406C>T) 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.Pro136Ser (c.406C>T) in the general population?

COL5A1 p.Pro136Ser (c.406C>T) is very rare (popmax 0.00593%, nfe) (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.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely pathogenic (score 0.8106) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro136Ser

c.406C>T · rs777625241 · VCV209143

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.8106	likely pathogenic
REVEL	0.638	indeterminate
SaProt	LLR -12.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.35, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 96 kb · p 0.17 · regional, not allelic
Overall
CADD	24.0	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 0.00593% European (non-Finnish) · 70/1,180,040 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00452% 73/1,613,474 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00593%	16,858
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Pro136Ser
Coding: c.406C>T
MANE Select: NM_000093
dbSNP: rs777625241
Type: single nucleotide variant
Location: chr9:134700037 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 136: the laminin g-like domain

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.Pro136= Benign/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
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-pro136ser (accessed [today's date]).

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