# NM_001258392.3(CLPB):c.1468C>T (p.Arg490Cys)

https://sugi.bio/variant/clpb-p-arg490cys

## Summary

**CLPB p.Arg490Cys (c.1468C>T)** is classified **Uncertain significance** in CLPB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely benign (0.3288); Very rare (popmax 0.00439%, sas); Associated with 3-methylglutaconic aciduria, type VIIB.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773040549 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the CLPB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to 3-methylglutaconic aciduria, type VIIB.

*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) | Antenatal, Neonatal |
| Diagnostic panels | CLPB is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal cyst — Very frequent (99-80%)
- Nephrocalcinosis — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Decreased total neutrophil count — Very frequent (99-80%)
- 3-Methylglutaconic aciduria — Very frequent (99-80%)
- Congenital microcephaly — Very frequent (99-80%)
- Intellectual disability — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017767/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLPB](https://sugi.bio/atlas/gene/CLPB/) |
| Protein change (HGVS p.) | p.Arg490Cys |
| Coding change (HGVS c.) | c.1468C>T |
| MANE Select transcript | [NM_001258392](https://www.ncbi.nlm.nih.gov/nuccore/NM_001258392) |
| dbSNP | [rs773040549](https://www.ncbi.nlm.nih.gov/snp/rs773040549/) |
| Variant type | single nucleotide variant |
| Location | chr11:72295510-72295510 (GRCh38) |
| ClinVar | [VCV1019403](https://www.ncbi.nlm.nih.gov/clinvar/variation/1019403/) |

**All HGVS expressions:** `LRG_1338:g.144175C>T`, `LRG_1338t1:c.1468C>T`, `NC_000011.10:g.72295510G>A`, `NC_000011.9:g.72006554G>A`, `NG_042130.2:g.144175C>T`, `NM_001258392.3:c.1468C>T`, `NM_001258393.3:c.1381C>T`, `NM_001258394.3:c.1423C>T`, `NM_030813.6:c.1558C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3288)
- REVEL 0.369 (indeterminate)
- SaProt LLR -9.946 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 9.585, GERP 1.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R520C** vs ClinVar **R490C**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 33.0**. 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 0.89** across the covering region of the MANE Select transcript (72,293,370–72,295,620), spanning 2,250 bp. Chi-square p 0.067. 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>C, Δ0.83 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 **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,066 in the highest group · 14/1,614,016 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,766 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,021 |
| Admixed American | 0.00167% | 59,994 |
| European (non-Finnish) | 0.000593% | 168,575 |

*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}

**CLPB** population constraint: LOEUF 0.643, pLI 0.00035321, missense-Z 1.6433. *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):

- **Leigh syndrome** — Limited (AR)

## Protein context {#protein}

Residue **490** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 72.52, 26% of residues very-high.

**7 experimental structure(s)** (PDB): [7TTR](https://www.rcsb.org/structure/7TTR), [7TTS](https://www.rcsb.org/structure/7TTS), [7US2](https://www.rcsb.org/structure/7US2), [7XBK](https://www.rcsb.org/structure/7XBK), [7XC5](https://www.rcsb.org/structure/7XC5), [8DEH](https://www.rcsb.org/structure/8DEH).

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

*Describes the biological roles of CLPB (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:** CLPB's established molecular role includes ATP hydrolysis activity.


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

**Molecular function:** ATP hydrolysis activity, ATP-dependent protein disaggregase activity.

**Biological process:** granulocyte differentiation, cellular response to heat, RIG-I signaling pathway, antiviral innate immune response.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-26 |

## Associated conditions {#conditions}

[3-methylglutaconic aciduria, type VIIB](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-viib/).

**Reported phenotype names (ClinVar):** 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia, 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, CLPB Deficiency.

## Similar variants {#similar}

Related CLPB variant pages (same residue, condition, or type): [CLPB p.Arg490His](/variant/clpb-p-arg490his), [CLPB c.1066+1G>A](/variant/clpb-c-1066-plus-1g-a), [CLPB c.455+1G>A](/variant/clpb-c-455-plus-1g-a), [CLPB c.873+1G>A](/variant/clpb-c-873-plus-1g-a), [CLPB c.874-2A>G](/variant/clpb-c-874-minus-2a-g), [CLPB p.Arg178Ter](/variant/clpb-p-arg178ter), [CLPB p.Arg312Ter](/variant/clpb-p-arg312ter), [CLPB p.Arg378Gly](/variant/clpb-p-arg378gly).

### 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 1019403). 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.*