# NM_006012.4(CLPP):c.441C>T (p.Cys147=)

https://sugi.bio/variant/clpp-p-cys147

## Summary

**CLPP p.Cys147= (c.441C>T)** is classified **Likely benign** in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). Very rare (popmax 0.00223%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs752826199 · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CLPP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Cys147= |
| Coding change (HGVS c.) | c.441C>T |
| MANE Select transcript | [NM_006012](https://www.ncbi.nlm.nih.gov/nuccore/NM_006012) |
| dbSNP | [rs752826199](https://www.ncbi.nlm.nih.gov/snp/rs752826199/) |
| Variant type | single nucleotide variant |
| Location | chr19:6364525-6364525 (GRCh38) |
| ClinVar | [VCV2998411](https://www.ncbi.nlm.nih.gov/clinvar/variation/2998411/) |

**All HGVS expressions:** `LRG_1402:g.8074C>T`, `LRG_1402t1:c.441C>T`, `NC_000019.10:g.6364525C>T`, `NC_000019.9:g.6364536C>T`, `NG_033887.1:g.8074C>T`, `NM_006012.4:c.441C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -6.189, GERP -4.47 — fast-evolving / accelerated position
- CADD: **PHRED 5.917**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.85 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 (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000803% · FAF99 0.00065% · 1/44,852 in the highest group · 18/1,612,522 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,852 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,408 |
| European (non-Finnish) | 0.00136% | 73,736 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **147** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CLPP p.Cys147Ser](/variant/clpp-p-cys147ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CLPP variant pages (same residue, condition, or type): [CLPP p.Cys147Ser](/variant/clpp-p-cys147ser), [CLPP c.368-2A>G](/variant/clpp-c-368-minus-2a-g), [CLPP p.Ala10Gly](/variant/clpp-p-ala10gly), [CLPP p.Ala10Ser](/variant/clpp-p-ala10ser), [CLPP p.Ala128Thr](/variant/clpp-p-ala128thr), [CLPP p.Ala223Thr](/variant/clpp-p-ala223thr), [CLPP p.Ala43Thr](/variant/clpp-p-ala43thr), [CLPP p.Ala50Thr](/variant/clpp-p-ala50thr).

### 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 2998411). 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.*