Is COL18A1 p.Val646= (c.1938G>T) pathogenic?

COL18A1 p.Val646= (c.1938G>T) is classified Conflicting classifications of pathogenicity in COL18A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-01). Very rare (popmax 0.00221%, nfe); Associated with Knobloch syndrome.

What condition is associated with COL18A1 p.Val646= (c.1938G>T)?

COL18A1 p.Val646= (c.1938G>T) is associated with Knobloch syndrome (ClinVar).

How common is COL18A1 p.Val646= (c.1938G>T) in the general population?

COL18A1 p.Val646= (c.1938G>T) is very rare (popmax 0.00221%, nfe) (gnomAD).

COL18A1 p.Val646=

c.1938G>T · rs886057125 · VCV340230

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

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 -1.7	GERP -2.5
Overall
CADD	0.159	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% European (non-Finnish) · 26/1,175,018 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00131%

Overall 0.00187% 30/1,603,312 alleles · very rare exomes 28/1,451,142 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00321%	31,117
European (non-Finnish)grpmax	0.00221%	45,193
Admixed American	0.00169%	59,064
Remaining individualsnot grpmax-eligible	0.00161%	61,998

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val646=
Coding: c.1938G>T
MANE Select: NM_001379500
dbSNP: rs886057125
Type: single nucleotide variant
Location: chr21:45489500 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 646: the 'disordered' region; the 'nonhelical region 1 (nc1)' 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 p.Val646Met Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-val646 (accessed [today's date]).

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