Is COMP p.Cys292Ter (c.876C>A) pathogenic?

COMP p.Cys292Ter (c.876C>A) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). Very rare (popmax 0.000339%, nfe); Associated with COMP-related disorder.

What condition is associated with COMP p.Cys292Ter (c.876C>A)?

COMP p.Cys292Ter (c.876C>A) is associated with COMP-related disorder (ClinVar).

How common is COMP p.Cys292Ter (c.876C>A) in the general population?

COMP p.Cys292Ter (c.876C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

COMP p.Cys292Ter

c.876C>A · rs923884041 · VCV891983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

COMP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 19
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.7	GERP 0.86, phastCons 1
Overall
CADD	39.0	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 0.000339% European (non-Finnish) · 4/1,179,784 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,459,386 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.Cys292Ter
Coding: c.876C>A
MANE Select: NM_000095
dbSNP: rs923884041
Type: single nucleotide variant
Location: chr19:18788311 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 292: a β-strand; a disulfide bond

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

Disease context

COMP-related disorder

Similar variants

COMP p.Cys292Arg Pathogenic/Likely pathogenic ★★ same residue
COMP p.Cys292Phe Pathogenic ★ same residue
COMP p.Cys292Tyr Likely pathogenic ★ same residue
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp401Asn Pathogenic ★★ same condition
COMP p.Asp458Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp507Gly Pathogenic/Likely pathogenic ★★ 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/comp-p-cys292ter (accessed [today's date]).

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