Is COMP c.2227+8G>A pathogenic?

COMP c.2227+8G>A is classified Benign/Likely benign in COMP (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-11). Low-frequency (popmax 4.59%, afr); Associated with connective tissue disorder.

What condition is associated with COMP c.2227+8G>A?

COMP c.2227+8G>A is associated with connective tissue disorder, multiple epiphyseal dysplasia type 1, pseudoachondroplasia (ClinVar).

How common is COMP c.2227+8G>A in the general population?

COMP c.2227+8G>A is low-frequency (popmax 4.59%, afr) (gnomAD).

COMP c.2227+8G>A

rs116499541 · VCV328609

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.59%, afr)

Conditions

connective tissue disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.6	GERP -3
Non-coding constraint	Z 1.81	1 kb window · o/e 0.84 · regional · uncalibrated
Overall
CADD	2.694	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.59% African / African-American · 3,447/75,054 alleles

Filtering AF 4.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.41%

Overall 0.25% 4,037/1,612,206 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.59%	22
Admixed American	0.33%	303
Remaining individualsnot grpmax-eligible	0.293%	342
Middle Eastern	0.182%	551
European (non-Finnish)	0.0158%	6,344
South Asian	0.011%	9,108
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802

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
Coding: c.2227+8G>A
MANE Select: NM_000095
dbSNP: rs116499541
Type: single nucleotide variant
Location: chr19:18783046 (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

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia type 1 pseudoachondroplasia

Similar variants

COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp273Val Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp349His 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-c-2227-plus-8g-a (accessed [today's date]).

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