Is COL18A1 p.Pro976fs (c.2927_2978del) pathogenic?

COL18A1 p.Pro976fs (c.29272978del) is classified Pathogenic in COL18A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). Very rare (popmax 8.5e-05%, nfe).

How common is COL18A1 p.Pro976fs (c.2927_2978del) in the general population?

COL18A1 p.Pro976fs (c.2927_2978del) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

COL18A1 p.Pro976fs

c.2927_2978del · rs2037118140 · VCV1416390

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 35 of 42
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.14	GERP -2.5, phastCons 0.008

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,720 alleles

Overall 6.23e-05% 1/1,604,146 alleles · very rare exomes 1/1,453,046 · genomes 0/151,100 · 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: COL18A1
Protein: p.Pro976fs
Coding: c.2927_2978del
MANE Select: NM_001379500
dbSNP: rs2037118140
Type: Deletion
Location: chr21:45505188 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 976: the 'triple-helical region 3 (col3)' region; the 'disordered' region

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

Similar variants

COL18A1 p.Pro976= Likely benign ★★ same residue
COL18A1 p.Pro976Ser Uncertain significance ★ ⚠ same residue
COL18A1 p.Ala783fs Pathogenic ★★ same type
COL18A1 p.Gly387fs Pathogenic ★★ same type
COL18A1 p.Gly942fs Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Ile1182fs Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Pro1012fs Pathogenic ★★ same type
COL18A1 p.Pro1015fs Pathogenic/Likely pathogenic ★★ 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/col18a1-p-pro976fs (accessed [today's date]).

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