Is CLPP p.Ala10fs (c.21del) pathogenic?

CLPP p.Ala10fs (c.21del) is classified Pathogenic in CLPP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-01). Very rare (popmax 0.000462%, nfe); Associated with Perrault syndrome 3.

What condition is associated with CLPP p.Ala10fs (c.21del)?

CLPP p.Ala10fs (c.21del) is associated with Perrault syndrome 3 (ClinVar).

How common is CLPP p.Ala10fs (c.21del) in the general population?

CLPP p.Ala10fs (c.21del) is very rare (popmax 0.000462%, nfe) (gnomAD).

How is Perrault syndrome inherited?

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

CLPP p.Ala10fs

c.21del · rs756490492 · VCV2138190

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000462%, nfe)

Conditions

Perrault syndrome 3

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 1 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.56	GERP -2.2, phastCons 0.21
Overall
CADD	11.95	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 0.000462% European (non-Finnish) · 5/1,082,024 alleles

Filtering AF 0.000135% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.8e-05%

Overall 0.000425% 6/1,412,892 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00186%	53,764
European (non-Finnish)grpmax	0.000462%	216,405

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: CLPP
Protein: p.Ala10fs
Coding: c.21del
MANE Select: NM_006012
dbSNP: rs756490492
Type: Deletion
Location: chr19:6361595 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 32 PDB

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.Ala10Gly Uncertain significance ★★ ⚠ same residue
CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same residue
CLPP p.Ser110fs Pathogenic ★ same condition
CLPP p.Ala10= Likely benign ★ same residue
CLPP c.-995_270+222del Likely pathogenic same condition
CLPP c.368-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLPP p.Arg174Cys Uncertain significance ★★ ⚠ same condition
CLPP p.Val264Ala 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/clpp-p-ala10fs (accessed [today's date]).

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