Is COMP p.Arg718Pro (c.2153G>C) pathogenic?

COMP p.Arg718Pro (c.2153G>C) is classified Pathogenic in COMP (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-08). AlphaMissense: likely pathogenic (0.9153); Absent from gnomAD v4.1; Associated with multiple epiphyseal dysplasia.

What condition is associated with COMP p.Arg718Pro (c.2153G>C)?

COMP p.Arg718Pro (c.2153G>C) is associated with multiple epiphyseal dysplasia (ClinVar).

How common is COMP p.Arg718Pro (c.2153G>C) in the general population?

COMP p.Arg718Pro (c.2153G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COMP p.Arg718Pro (c.2153G>C)?

AlphaMissense predicts likely pathogenic (score 0.9153) — an in-silico prediction, not a clinical call.

COMP p.Arg718Pro

c.2153G>C · rs149551600 · VCV65557

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9153 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple epiphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.9153	likely pathogenic ✓ concordant with ClinVar
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COMP
Protein: p.Arg718Pro
Coding: c.2153G>C
MANE Select: NM_000095
dbSNP: rs149551600
Type: single nucleotide variant
Location: chr19:18783128 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 718: a UniProt-annotated variant site (in edm1); a UniProt-annotated variant site (in edm1 and cts2; reduced secretion in tendon cells and chondrocytes); the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a β-strand; a disulfide bond

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

Disease context

multiple epiphyseal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
COMP p.Arg718= Benign/Likely benign ★★ same residue
COMP p.Arg718Gln Uncertain significance ★ ⚠ same residue
COMP p.Asp385Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Gly501Ser Likely pathogenic ★★ same condition
COMP p.Thr585Met Pathogenic ★★ same condition
COMP p.Thr585Arg Pathogenic ★ same condition
COMP p.Asp605Asn Uncertain significance ★ ⚠ 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-arg718pro (accessed [today's date]).

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