Is COL18A1 p.Pro1012= (c.3036G>A) pathogenic?

COL18A1 p.Pro1012= (c.3036G>A) is classified Benign/Likely benign in COL18A1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). Rare (popmax 0.385%, nfe); Associated with Knobloch syndrome 1.

What condition is associated with COL18A1 p.Pro1012= (c.3036G>A)?

COL18A1 p.Pro1012= (c.3036G>A) is associated with Knobloch syndrome 1, hereditary glaucoma, primary closed-angle (ClinVar).

How common is COL18A1 p.Pro1012= (c.3036G>A) in the general population?

COL18A1 p.Pro1012= (c.3036G>A) is rare (popmax 0.385%, nfe) (gnomAD).

COL18A1 p.Pro1012=

c.3036G>A · rs370656151 · VCV447125

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.385%, nfe)

Conditions

Knobloch syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.034	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.2
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.385% European (non-Finnish) · 4,464/1,158,822 alleles

Filtering AF 0.376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.313% 4,971/1,585,962 alleles · rare exomes 4,637/1,433,936 · genomes 334/152,026 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.385%	260
Remaining individualsnot grpmax-eligible	0.324%	309
Admixed American	0.191%	525
Finnishnot grpmax-eligible	0.143%	701
Middle Eastern	0.0786%	1,273
African / African-American	0.0604%	1,656
South Asian	0.0512%	1,952
East Asian	0.0224%	4,461
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,142

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: COL18A1
Protein: p.Pro1012=
Coding: c.3036G>A
MANE Select: NM_001379500
dbSNP: rs370656151
Type: single nucleotide variant
Location: chr21:45505380 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1012: the 'triple-helical region 3 (col3)' region; the 'disordered' region

Full COL18A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Knobloch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary glaucoma, primary closed-angle

Similar variants

COL18A1 p.Pro1012Leu Uncertain significance ★★ ⚠ same residue
COL18A1 c.2577+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL18A1 c.3013+3A>C Likely pathogenic ★★ same condition
COL18A1 c.798+1G>T Likely pathogenic ★★ same condition
COL18A1 p.Arg487Ter Pathogenic ★★ same condition
COL18A1 p.Pro1012fs Pathogenic ★★ same residue
COL18A1 c.107-12131C>T Uncertain significance ★★ ⚠ same condition
COL18A1 c.1311+5G>C 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/col18a1-p-pro1012 (accessed [today's date]).

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