Is COMP p.Thr660fs (c.1979_1980del) pathogenic?

COMP p.Thr660fs (c.19791980del) is classified Uncertain significance in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). Very rare (popmax 0.0011%, sas).

How common is COMP p.Thr660fs (c.1979_1980del) in the general population?

COMP p.Thr660fs (c.1979_1980del) is very rare (popmax 0.0011%, sas) (gnomAD).

COMP p.Thr660fs

c.1979_1980del · rs760514744 · VCV2122673

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 0.0011%, sas)

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 0.018	GERP -4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000752% 11/1,461,808 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000763%	131,116

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr660fs
Coding: c.1979_1980del
MANE Select: NM_000095
dbSNP: rs760514744
Type: Microsatellite
Location: chr19:18784298 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 1 PDB
Residue 660: the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a disulfide bond

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

Similar variants

COMP p.Thr660Ala Uncertain significance ★★ ⚠ same residue
COMP p.Thr660Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
COMP p.Thr660Pro 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

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-thr660fs (accessed [today's date]).

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