Is COL8A2 p.Pro526fs (c.1576_1583del) pathogenic?

COL8A2 p.Pro526fs (c.15761583del) is classified Uncertain significance in COL8A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). Very rare (popmax 8.73e-05%, nfe); Associated with posterior polymorphous corneal dystrophy 2.

What condition is associated with COL8A2 p.Pro526fs (c.1576_1583del)?

COL8A2 p.Pro526fs (c.1576_1583del) is associated with posterior polymorphous corneal dystrophy 2 (ClinVar).

How common is COL8A2 p.Pro526fs (c.1576_1583del) in the general population?

COL8A2 p.Pro526fs (c.1576_1583del) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

How is Posterior polymorphous corneal dystrophy inherited?

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

COL8A2 p.Pro526fs

c.1576_1583del · VCV3779152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Conditions

posterior polymorphous corneal dystrophy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.9	GERP -4.2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.73e-05% European (non-Finnish) · 1/1,145,722 alleles

Overall 6.55e-05% 1/1,526,368 alleles · very rare exomes 1/1,375,002 · genomes 0/151,366 · joint denominator

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: COL8A2
Protein: p.Pro526fs
Coding: c.1576_1583del
MANE Select: NM_005202
Type: Deletion
Location: chr1:36098098 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.03
Residue 526: the 'disordered' region; the 'triple-helical region' region

Full COL8A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

posterior polymorphous corneal dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Posterior polymorphous corneal dystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 100 000 (Czech Republic)

Similar variants

COL8A2 p.Pro526Ser Uncertain significance ★ ⚠ same residue
COL8A2 p.Pro526Thr Uncertain significance ★ ⚠ same residue
COL8A2 p.Pro291Gln Uncertain significance ★★ ⚠ same condition
COL8A2 c.193+34C>T Benign ★★ same condition
COL8A2 c.*12G>T Benign ★★ same condition
COL8A2 p.Leu450Trp Pathogenic ★ ⚠ same condition
COL8A2 p.Gln455Lys Pathogenic ⚠ same condition
COL8A2 p.520PPG[3] Uncertain significance ★ same type

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/col8a2-p-pro526fs (accessed [today's date]).

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