Is COMP p.Arg718Trp (c.2152C>T) pathogenic?

COMP p.Arg718Trp (c.2152C>T) is classified Pathogenic/Likely pathogenic in COMP (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.3785); Very rare (popmax 0.000169%, nfe); Associated with multiple epiphyseal dysplasia type 1.

What condition is associated with COMP p.Arg718Trp (c.2152C>T)?

COMP p.Arg718Trp (c.2152C>T) is associated with multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia, carpal tunnel syndrome 2 (ClinVar).

How common is COMP p.Arg718Trp (c.2152C>T) in the general population?

COMP p.Arg718Trp (c.2152C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Multiple epiphyseal dysplasia type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COMP p.Arg718Trp (c.2152C>T)?

AlphaMissense predicts ambiguous (score 0.3785) — an in-silico prediction, not a clinical call.

COMP p.Arg718Trp

c.2152C>T · rs28936368 · VCV9198

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

multiple epiphyseal dysplasia type 1

Computational evidence

Protein change
AlphaMissense	0.3785	ambiguous
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -13.05	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.1	GERP -3.5, phastCons 0.79
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,998 alleles

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

Overall 0.000137% 2/1,458,542 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.Arg718Trp
Coding: c.2152C>T
MANE Select: NM_000095
dbSNP: rs28936368
Type: single nucleotide variant
Location: chr19:18783129 (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 type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple epiphyseal dysplasia carpal tunnel syndrome 2

For Multiple epiphyseal dysplasia type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

COMP p.Arg718= Benign/Likely benign ★★ same residue
COMP p.Arg718Pro Pathogenic ★ ⚠ same residue
COMP p.Arg718Gln Uncertain significance ★ ⚠ same residue
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.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp385Asn 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-arg718trp (accessed [today's date]).

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