Is COMP p.Ala133fs (c.397_398del) pathogenic?

COMP p.Ala133fs (c.397398del) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). Very rare (popmax 8.89e-05%, nfe).

How common is COMP p.Ala133fs (c.397_398del) in the general population?

COMP p.Ala133fs (c.397_398del) is very rare (popmax 8.89e-05%, nfe) (gnomAD).

COMP p.Ala133fs

c.397_398del · rs2145904172 · VCV1514131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.89e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.057	GERP -3.7, phastCons 0.18

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.89e-05% European (non-Finnish) · 1/1,124,278 alleles

Overall 7.46e-05% 1/1,340,734 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.Ala133fs
Coding: c.397_398del
MANE Select: NM_000095
dbSNP: rs2145904172
Type: Deletion
Location: chr19:18789290 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 133: the egf-like 2; calcium-binding domain; a disulfide bond

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

Similar variants

COMP p.Ala133= Likely benign ★ same residue
COMP p.Asp385del Likely pathogenic ★★ same type
COMP p.Glu341_Asp342del Pathogenic/Likely pathogenic ★★ same type
COMP c.1136-1_1144del Likely pathogenic ★ same type
COMP p.437DG[1] Likely pathogenic ★ same type
COMP p.Asn350_Asp372del Likely pathogenic ★ same type
COMP p.Asn474_Asp475del Likely pathogenic ★ same type
COMP p.Asp509_Ala510delinsGlu 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-ala133fs (accessed [today's date]).

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