Is COMP p.Ter758Gln (c.2272T>C) pathogenic?

COMP p.Ter758Gln (c.2272T>C) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). Very rare (popmax 0.000169%, nfe); Associated with COMP-related disorder.

What condition is associated with COMP p.Ter758Gln (c.2272T>C)?

COMP p.Ter758Gln (c.2272T>C) is associated with COMP-related disorder (ClinVar).

How common is COMP p.Ter758Gln (c.2272T>C) in the general population?

COMP p.Ter758Gln (c.2272T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

COMP p.Ter758Gln

c.2272T>C · rs2055134120 · VCV890687

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

COMP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -0.53, phastCons 1
Overall
CADD	16.08	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 0.000169% European (non-Finnish) · 2/1,179,960 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,490 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	0.000169%	589,981

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: COMP
Protein: p.Ter758Gln
Coding: c.2272T>C
MANE Select: NM_000095
dbSNP: rs2055134120
Type: single nucleotide variant
Location: chr19:18782917 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB

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

Disease context

COMP-related disorder

Similar variants

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
COMP p.Asp518His Pathogenic/Likely pathogenic ★★ same condition
COMP p.Cys484Gly Likely pathogenic ★★ same condition
COMP p.Gly501Asp 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-ter758gln (accessed [today's date]).

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