Is COL18A1 p.Val42= (c.126G>A) pathogenic?

COL18A1 p.Val42= (c.126G>A) is classified Benign in COL18A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Low-frequency (popmax 3.55%, afr); Associated with Knobloch syndrome.

What condition is associated with COL18A1 p.Val42= (c.126G>A)?

COL18A1 p.Val42= (c.126G>A) is associated with Knobloch syndrome (ClinVar).

How common is COL18A1 p.Val42= (c.126G>A) in the general population?

COL18A1 p.Val42= (c.126G>A) is low-frequency (popmax 3.55%, afr) (gnomAD).

COL18A1 p.Val42=

c.126G>A · rs115800039 · VCV340191

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.55%, afr)

Conditions

Knobloch syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.88, phastCons 1
Overall
CADD	5.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.55% African / African-American · 2,667/75,072 alleles

Filtering AF 3.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.39%

Overall 0.187% 3,019/1,613,060 alleles · low-frequency exomes 1,431/1,460,690 · genomes 1,588/152,370 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.55%	28
Admixed American	0.282%	355
Remaining individualsnot grpmax-eligible	0.216%	463
Middle Eastern	0.0825%	1,212
European (non-Finnish)	0.00339%	29,501
South Asian	0.00329%	30,362

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.Val42=
Coding: c.126G>A
MANE Select: NM_001379500
dbSNP: rs115800039
Type: single nucleotide variant
Location: chr21:45468261 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 42: the 'disordered' region

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

Disease context

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

Similar variants

COL18A1 c.3013+3A>C Likely pathogenic ★★ same condition
COL18A1 c.3809+2T>C Pathogenic ★★ same condition
COL18A1 p.Arg790Ter Pathogenic ★★ same condition
COL18A1 c.107-11479C>A Uncertain significance ★★ ⚠ same condition
COL18A1 c.107-12131C>T Uncertain significance ★★ ⚠ same condition
COL18A1 c.1311+5G>C Uncertain significance ★★ same condition
COL18A1 c.799-3C>G Uncertain significance ★★ same condition
COL18A1 p.Ala1156Thr 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-val42 (accessed [today's date]).

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