Is COL18A1 p.Phe476= (c.1428C>T) pathogenic?

COL18A1 p.Phe476= (c.1428C>T) is classified Benign in COL18A1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 27.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Knobloch syndrome.

What condition is associated with COL18A1 p.Phe476= (c.1428C>T)?

COL18A1 p.Phe476= (c.1428C>T) is associated with Knobloch syndrome (ClinVar).

COL18A1 p.Phe476=

Q: How common is COL18A1 p.Phe476= (c.1428C>T) in the general population?

COL18A1 p.Phe476= (c.1428C>T) is common (popmax 27.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1428C>T · rs2236467 · VCV340221

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 27.1%, afr) — too common for a highly-penetrant pathogenic allele

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 -2.4	GERP -1.7
Overall
CADD	6.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.1% African / African-American · 20,313/74,952 alleles

Filtering AF 26.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.7%

Overall 7.87% 127,087/1,614,008 alleles · common exomes 108,469/1,461,834 · genomes 18,618/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	27.1%	4
East Asian	13.5%	7
South Asian	12.4%	8
Middle Eastern	9.55%	10
Remaining individualsnot grpmax-eligible	8.7%	11
European (non-Finnish)	6.49%	15
Admixed American	6.42%	16
Ashkenazi Jewishnot grpmax-eligible	5.1%	20
Amishnot grpmax-eligible	3.73%	27
Finnishnot grpmax-eligible	2.16%	46

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.Phe476=
Coding: c.1428C>T
MANE Select: NM_001379500
dbSNP: rs2236467
Type: single nucleotide variant
Location: chr21:45480496 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 476: the laminin g-like domain

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-phe476 (accessed [today's date]).

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