# NM_006012.4(CLPP):c.440G>C (p.Cys147Ser)

https://sugi.bio/variant/clpp-p-cys147ser

## Summary

**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.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs398123034 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CLPP gene that is reported as disease-causing, but on limited review, submitted by 3 submitters, and is linked to Perrault syndrome 3.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | CLPP is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Perrault syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Increased circulating gonadotropin level — Very frequent (99-80%)
- Hypoplasia of the uterus — Frequent (79-30%)
- Primary amenorrhea — Frequent (79-30%)
- Premature ovarian insufficiency — Frequent (79-30%)
- Streak ovary — Frequent (79-30%)
- Azoospermia — Occasional (29-5%)
- Cleft palate — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015760/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLPP](https://sugi.bio/atlas/gene/CLPP/) |
| Protein change (HGVS p.) | p.Cys147Ser |
| Coding change (HGVS c.) | c.440G>C |
| MANE Select transcript | [NM_006012](https://www.ncbi.nlm.nih.gov/nuccore/NM_006012) |
| dbSNP | [rs398123034](https://www.ncbi.nlm.nih.gov/snp/rs398123034/) |
| Variant type | single nucleotide variant |
| Location | chr19:6364524-6364524 (GRCh38) |
| ClinVar | [VCV55869](https://www.ncbi.nlm.nih.gov/clinvar/variation/55869/) |

**All HGVS expressions:** `LRG_1402:g.8073G>C`, `LRG_1402t1:c.440G>C`, `NC_000019.10:g.6364524G>C`, `NC_000019.9:g.6364535G>C`, `NG_033887.1:g.8073G>C`, `NM_006012.4:c.440G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9356) — concordant with the pathogenic call
- REVEL 0.7 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.12 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.698, GERP 2.23, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.76** across the covering region of the MANE Select transcript (6,361,904–6,368,707), spanning 6,803 bp. Chi-square p 5e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.43 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CLPP** population constraint: LOEUF 0.936, pLI 0.0061632, missense-Z 0.12828; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Perrault syndrome 3** — Definitive (AR)

## Protein context {#protein}

Residue **147** lies in a β-strand; a UniProt-annotated variant site (in prlts3).

AlphaFold model confidence (whole protein): pLDDT 82.68, 62% of residues very-high.

**32 experimental structure(s)** (PDB): [1TG6](https://www.rcsb.org/structure/1TG6), [6BBA](https://www.rcsb.org/structure/6BBA), [6DL7](https://www.rcsb.org/structure/6DL7), [6H23](https://www.rcsb.org/structure/6H23), [7UVM](https://www.rcsb.org/structure/7UVM), [7UVN](https://www.rcsb.org/structure/7UVN) — incl. mutant structure 6H23.

## What this gene does {#gene-function}

*Describes the biological roles of CLPP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CLPP's established molecular role includes endopeptidase activity.


### Pathways affected {#pathways}

CLPP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** endopeptidase activity, serine-type endopeptidase activity.

**Biological process:** proteolysis, membrane protein proteolysis, obsolete proteolysis involved in protein catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2013-06-17.

**Submitter consensus:** conflicting (2 Pathogenic, 1 not provided).

**Submission history:** 3 submissions (2013); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Molecular and Human Genetics, Baylor College of Medicine | Pathogenic | no assertion criteria provided | research | 2013-06-17 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-04-04 |
| GeneReviews | not provided | no classification provided | literature only |  |

## Associated conditions {#conditions}

[Perrault syndrome 3](https://sugi.bio/atlas/disease/perrault-syndrome-3/), [Perrault syndrome](https://sugi.bio/atlas/disease/perrault-syndrome/).

**Reported phenotype names (ClinVar):** Perrault syndrome 3, Perrault syndrome, Gonadal dysgenesis with auditory dysfunction, autosomal recessive inheritance.

## Similar variants {#similar}

Related CLPP variant pages (same residue, condition, or type): [CLPP p.Cys147=](/variant/clpp-p-cys147), [CLPP c.368-2A>G](/variant/clpp-c-368-minus-2a-g), [CLPP p.Arg174Cys](/variant/clpp-p-arg174cys), [CLPP p.Val264Ala](/variant/clpp-p-val264ala), [CLPP c.555+16G>A](/variant/clpp-c-555-plus-16g-a), [CLPP c.-5G>A](/variant/clpp-c-minus-5g-a), [CLPP c.661+2T>G](/variant/clpp-c-661-plus-2t-g), [CLPP p.Arg78Pro](/variant/clpp-p-arg78pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 55869). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*