Is COMP p.Cys266fs (c.798_799del) pathogenic?

COMP p.Cys266fs (c.798799del) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). Very rare (popmax 0.000933%, nfe).

How common is COMP p.Cys266fs (c.798_799del) in the general population?

COMP p.Cys266fs (c.798_799del) is very rare (popmax 0.000933%, nfe) (gnomAD).

COMP p.Cys266fs

c.798_799del · rs2055186665 · VCV1372574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000933%, 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 8 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,136 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000683% 11/1,610,560 alleles · very rare

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: COMP
Protein: p.Cys266fs
Coding: c.798_799del
MANE Select: NM_000095
dbSNP: rs2055186665
Type: Microsatellite
Location: chr19:18788478 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 266: a disulfide bond; the egf-like 4 domain

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

Similar variants

COMP p.Cys266Arg Uncertain significance ★ ⚠ same residue
COMP p.Asp374del Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp473del Pathogenic ★★ same type
COMP p.Asp473dup Pathogenic/Likely pathogenic ★★ same type
COMP p.Glu457del Pathogenic/Likely pathogenic ★★ same type
COMP p.Gly320_Val321insAspGly Likely pathogenic ★ same type
COMP p.Asp374_Ile375insAsp Uncertain significance ★ same type
COMP p.Asp471_Asp473del Uncertain significance ★ 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/comp-p-cys266fs (accessed [today's date]).

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