Is COMP p.Arg285Leu (c.854G>T) pathogenic?

COMP p.Arg285Leu (c.854G>T) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-20). AlphaMissense: likely benign (0.1286); Ultra-rare (popmax 0.0383%, mid).

How common is COMP p.Arg285Leu (c.854G>T) in the general population?

COMP p.Arg285Leu (c.854G>T) is ultra-rare (popmax 0.0383%, mid) (gnomAD).

What do computational predictors say about COMP p.Arg285Leu (c.854G>T)?

AlphaMissense predicts likely benign (score 0.1286) — an in-silico prediction, not a clinical call.

COMP p.Arg285Leu

c.854G>T · VCV3626643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1286 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1286	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.035	GERP -4, phastCons 0.004
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	16.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0383% Middle Eastern · 2/5,216 alleles

Filtering AF 0.00679% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00284%

Overall 0.000834% 12/1,438,414 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0383%	2,608
Admixed American	0.00726%	13,779
European (non-Finnish)	0.000561%	178,292

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.Arg285Leu
Coding: c.854G>T
MANE Select: NM_000095
Type: single nucleotide variant
Location: chr19:18788423 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 285: an α-helix; a disulfide bond; a UniProt-annotated variant site (sequence variant)

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

Similar variants

COMP p.Arg285His Uncertain significance ★ ⚠ same residue
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

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-arg285leu (accessed [today's date]).

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