Is CLPP p.Cys147Ser (c.440G>C) pathogenic?

CLPP p.Cys147Ser (c.440G>C) is classified Pathogenic in CLPP (ClinVar, No assertion criteria, 3 submitters; last evaluated 2013-06-17). AlphaMissense: likely pathogenic (0.9356); Absent from gnomAD v4.1; Associated with Perrault syndrome 3.

What condition is associated with CLPP p.Cys147Ser (c.440G>C)?

CLPP p.Cys147Ser (c.440G>C) is associated with Perrault syndrome 3, Perrault syndrome (ClinVar).

How common is CLPP p.Cys147Ser (c.440G>C) in the general population?

CLPP p.Cys147Ser (c.440G>C) 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.

What do computational predictors say about CLPP p.Cys147Ser (c.440G>C)?

AlphaMissense predicts likely pathogenic (score 0.9356) — an in-silico prediction, not a clinical call.

CLPP p.Cys147Ser

c.440G>C · rs398123034 · VCV55869

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9356 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Perrault syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9356	likely pathogenic ✓ concordant with ClinVar
REVEL	0.7	pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 6,803 bp · p 5e-05 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Cys147Ser
Coding: c.440G>C
MANE Select: NM_006012
dbSNP: rs398123034
Type: single nucleotide variant
Location: chr19:6364524 (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 147: a β-strand; a UniProt-annotated variant site (in prlts3)

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

Also linked: Perrault syndrome

For Perrault syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CLPP p.Cys147= Likely benign ★ 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-cys147ser (accessed [today's date]).

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