Is COMP p.Gly215Arg (c.643G>C) pathogenic?

COMP p.Gly215Arg (c.643G>C) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-15). AlphaMissense: likely pathogenic (0.7448); Very rare (popmax 0.00788%, amr); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Gly215Arg (c.643G>C)?

COMP p.Gly215Arg (c.643G>C) is associated with Inborn genetic diseases, multiple epiphyseal dysplasia type 1, pseudoachondroplasia (ClinVar).

How common is COMP p.Gly215Arg (c.643G>C) in the general population?

COMP p.Gly215Arg (c.643G>C) is very rare (popmax 0.00788%, amr) (gnomAD).

What do computational predictors say about COMP p.Gly215Arg (c.643G>C)?

AlphaMissense predicts likely pathogenic (score 0.7448) — an in-silico prediction, not a clinical call.

COMP p.Gly215Arg

c.643G>C · rs768437153 · VCV890213

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7448	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -16.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00788% Admixed American · 4/50,792 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00347%

Overall 0.00389% 60/1,542,008 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00788%	12,698
European (non-Finnish)	0.00489%	20,446

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.Gly215Arg
Coding: c.643G>C
MANE Select: NM_000095
dbSNP: rs768437153
Type: single nucleotide variant
Location: chr19:18788711 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 215: a disulfide bond; the egf-like 3; calcium-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia type 1 pseudoachondroplasia

Similar variants

COMP p.Gly215Asp Uncertain significance ★★ ⚠ same residue
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

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-gly215arg (accessed [today's date]).

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