Is COMP p.Arg381Leu (c.1142G>T) pathogenic?

COMP p.Arg381Leu (c.1142G>T) is classified Uncertain significance in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-12). AlphaMissense: likely benign (0.1053); Very rare (popmax 0.00224%, eas); Associated with Inborn genetic diseases.

What condition is associated with COMP p.Arg381Leu (c.1142G>T)?

COMP p.Arg381Leu (c.1142G>T) is associated with Inborn genetic diseases (ClinVar).

How common is COMP p.Arg381Leu (c.1142G>T) in the general population?

COMP p.Arg381Leu (c.1142G>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about COMP p.Arg381Leu (c.1142G>T)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

COMP p.Arg381Leu

c.1142G>T · rs144953891 · VCV3147929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.11	GERP -3.1, phastCons 0.003
Regional constraint	o/e 0.84	unconstrained · MANE · 8,351 bp · p 2.2e-07 · regional, not allelic
Overall
CADD	21.5	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 0.00224% East Asian · 1/44,700 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,611,570 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,700
African / African-American	0.00134%	74,698
European (non-Finnish)	0.000255%	392,890

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.Arg381Leu
Coding: c.1142G>T
MANE Select: NM_000095
dbSNP: rs144953891
Type: single nucleotide variant
Location: chr19:18786644 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 381: the 'disordered' region; a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COMP p.Arg381His Uncertain significance ★★ ⚠ same residue
COMP p.Arg381Gly Uncertain significance ★ ⚠ same residue
COMP p.Arg247Ser Uncertain significance ★★ ⚠ same condition
COMP p.Arg352Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg379Gln Uncertain significance ★★ ⚠ same condition
COMP p.Arg665Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg689Trp Uncertain significance ★★ ⚠ same condition
COMP p.Arg721His 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-arg381leu (accessed [today's date]).

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