# NM_006012.4(CLPP):c.355A>G (p.Ile119Val)

https://sugi.bio/variant/clpp-p-ile119val

## Summary

**CLPP p.Ile119Val (c.355A>G)** is classified **Uncertain significance** in CLPP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-22). AlphaMissense: likely benign (0.2241); Very rare (popmax 0.00187%, nfe); Associated with CLPP-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1319249207 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00187%, nfe)

## For patients & families {#patients}

This is a change in the CLPP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to CLPP-related disorder.

*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.Ile119Val |
| Coding change (HGVS c.) | c.355A>G |
| MANE Select transcript | [NM_006012](https://www.ncbi.nlm.nih.gov/nuccore/NM_006012) |
| dbSNP | [rs1319249207](https://www.ncbi.nlm.nih.gov/snp/rs1319249207/) |
| Variant type | single nucleotide variant |
| Location | chr19:6362530-6362530 (GRCh38) |
| ClinVar | [VCV3029167](https://www.ncbi.nlm.nih.gov/clinvar/variation/3029167/) |

**All HGVS expressions:** `LRG_1402:g.6079A>G`, `LRG_1402t1:c.355A>G`, `NC_000019.10:g.6362530A>G`, `NC_000019.9:g.6362541A>G`, `NG_033887.1:g.6079A>G`, `NG_140194.1:g.425A>G`, `NM_006012.4:c.355A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2241)
- REVEL 0.307 (indeterminate)
- SaProt LLR -6.235 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.86) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.939, GERP 2.05, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 35.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.86**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.86**.
- Pangolin: Δ**0.56** (gain), gain 0.56 / loss 0.04. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00187%** (nfe) · FAF95 0.00122% · FAF99 0.00104% · 22/1,178,834 in the highest group · 22/1,612,598 alleles overall — very rare (popmax 0.00187%, nfe).

*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 **119** lies in a β-strand.

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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-01-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-01-22 |

## Associated conditions {#conditions}

[CLPP-related disorder](https://sugi.bio/atlas/disease/clpp-related-disorder/).

**Reported phenotype names (ClinVar):** CLPP-related disorder, CLPP-related condition.

## Similar variants {#similar}

Related CLPP variant pages (same residue, condition, or type): [CLPP p.Tyr133His](/variant/clpp-p-tyr133his), [CLPP c.270+4A>G](/variant/clpp-c-270-plus-4a-g), [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).

### 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 3029167). 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.*