Is COMP p.Glu661fs (c.1982_1983del) pathogenic?

COMP p.Glu661fs (c.19821983del) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-07). Very rare (popmax 0.00267%, afr).

How common is COMP p.Glu661fs (c.1982_1983del) in the general population?

COMP p.Glu661fs (c.1982_1983del) is very rare (popmax 0.00267%, afr) (gnomAD).

COMP p.Glu661fs

c.1982_1983del · rs767395029 · VCV3023317

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 0.00267%, afr)

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 17 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP -4, phastCons 0.74
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,846 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,613,758 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,423
European (non-Finnish)	0.00229%	43,704
Admixed American	0.00167%	59,976

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.Glu661fs
Coding: c.1982_1983del
MANE Select: NM_000095
dbSNP: rs767395029
Type: Microsatellite
Location: chr19:18784295 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 661: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a turn; a disulfide bond

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

Similar variants

COMP p.Glu661Lys Uncertain significance ★★ ⚠ same residue
COMP p.Glu661Gly Uncertain significance ★ ⚠ same residue
COMP p.Asp374del Pathogenic/Likely pathogenic ★★ same type
COMP p.Asp473del Pathogenic ★★ same type
COMP p.Asp473dup Pathogenic/Likely pathogenic ★★ same type
COMP p.Glu457del Pathogenic/Likely pathogenic ★★ same type
COMP p.Gly320_Val321insAspGly Likely pathogenic ★ same type
COMP p.Asp374_Ile375insAsp Uncertain significance ★ 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-glu661fs (accessed [today's date]).

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