Is CLPP p.Glu221Ter (c.661G>T) pathogenic?

CLPP p.Glu221Ter (c.661G>T) is classified Pathogenic in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). Absent from gnomAD v4.1; Associated with Perrault syndrome 3.

What condition is associated with CLPP p.Glu221Ter (c.661G>T)?

CLPP p.Glu221Ter (c.661G>T) is associated with Perrault syndrome 3 (ClinVar).

How common is CLPP p.Glu221Ter (c.661G>T) in the general population?

CLPP p.Glu221Ter (c.661G>T) is absent from gnomAD v4.1 (gnomAD).

How is Perrault syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CLPP p.Glu221Ter

c.661G>T · VCV3601044

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Perrault syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (5 of 6, 0 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.79	donor gain · deltas
Pangolin	Δ0.71	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	59.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLPP
Protein: p.Glu221Ter
Coding: c.661G>T
MANE Select: NM_006012
Type: single nucleotide variant
Location: chr19:6366363 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 32 PDB
Residue 221: an α-helix

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

Disease context

Perrault syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Perrault syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CLPP p.Glu221Lys Likely pathogenic ★ same residue
CLPP c.368-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLPP p.Arg174Cys Uncertain significance ★★ ⚠ same condition
CLPP p.Val264Ala Uncertain significance ★★ ⚠ same condition
CLPP c.555+16G>A Benign/Likely benign ★★ same condition
CLPP c.-5G>A Benign ★★ same condition
CLPP c.661+2T>G Likely pathogenic ★ same condition
CLPP p.Arg78Pro Likely pathogenic ★ 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/clpp-p-glu221ter (accessed [today's date]).

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