Is COMP p.Gln492Pro (c.1475A>C) pathogenic?

COMP p.Gln492Pro (c.1475A>C) is classified Likely pathogenic in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-28). AlphaMissense: likely pathogenic (0.7627); Very rare (popmax 8.6e-05%, nfe); Associated with COMP-related disorder.

What condition is associated with COMP p.Gln492Pro (c.1475A>C)?

COMP p.Gln492Pro (c.1475A>C) is associated with COMP-related disorder (ClinVar).

How common is COMP p.Gln492Pro (c.1475A>C) in the general population?

COMP p.Gln492Pro (c.1475A>C) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about COMP p.Gln492Pro (c.1475A>C)?

AlphaMissense predicts likely pathogenic (score 0.7627) — an in-silico prediction, not a clinical call.

COMP p.Gln492Pro

c.1475A>C · rs1252223404 · VCV1224328

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COMP-related disorder

Computational evidence

Protein change
AlphaMissense	0.7627	likely pathogenic ✓ concordant with ClinVar
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -17.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	29.9	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 8.6e-05% European (non-Finnish) · 1/1,162,554 alleles

Overall 6.31e-05% 1/1,583,804 alleles · very rare exomes 1/1,435,038 · genomes 0/148,766 · joint denominator

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.Gln492Pro
Coding: c.1475A>C
MANE Select: NM_000095
dbSNP: rs1252223404
Type: single nucleotide variant
Location: chr19:18785979 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 492: the 'disordered' region

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

Disease context

COMP-related disorder

Similar variants

COMP p.Asn489Lys Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp326Asn Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp401Asn Pathogenic ★★ same condition
COMP p.Asp458Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp507Gly Pathogenic/Likely pathogenic ★★ same condition
COMP p.Asp518His Pathogenic/Likely pathogenic ★★ same condition
COMP p.Cys484Gly Likely pathogenic ★★ same condition
COMP p.Gly501Asp 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-gln492pro (accessed [today's date]).

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