Is COMP p.Gly220Arg (c.658G>C) pathogenic?

COMP p.Gly220Arg (c.658G>C) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-11). AlphaMissense: ambiguous (0.348); Very rare (popmax 0.00105%, nfe).

How common is COMP p.Gly220Arg (c.658G>C) in the general population?

COMP p.Gly220Arg (c.658G>C) is very rare (popmax 0.00105%, nfe) (gnomAD).

What do computational predictors say about COMP p.Gly220Arg (c.658G>C)?

AlphaMissense predicts ambiguous (score 0.348) — an in-silico prediction, not a clinical call.

COMP p.Gly220Arg

c.658G>C · rs1601057836 · VCV1485504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00105%, nfe)

Computational evidence

Protein change
AlphaMissense	0.348	ambiguous
REVEL	0.6	indeterminate
SaProt	LLR -7.11	tolerated
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	28.4	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

Grpmax group 0.00105% European (non-Finnish) · 12/1,144,820 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000442%

Overall 0.000864% 12/1,388,850 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.Gly220Arg
Coding: c.658G>C
MANE Select: NM_000095
dbSNP: rs1601057836
Type: single nucleotide variant
Location: chr19:18788696 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 220: a disulfide bond; the egf-like 3; calcium-binding domain

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

Similar variants

COMP p.Arg718Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn523Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asn555Lys Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp269Gly Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp273Val Likely pathogenic ★★ same type
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp349His Pathogenic ★★ same type

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-gly220arg (accessed [today's date]).

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