# NM_001258392.3(CLPB):c.1140C>T (p.Asp380=)

https://sugi.bio/variant/clpb-p-asp380

## Summary

**CLPB p.Asp380= (c.1140C>T)** is classified **Conflicting classifications of pathogenicity** in CLPB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0117%, amr); Associated with 3-methylglutaconic aciduria, type VIIB.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200950385 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the CLPB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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 |

**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.Asp380= |
| Coding change (HGVS c.) | c.1140C>T |
| dbSNP | [rs200950385](https://www.ncbi.nlm.nih.gov/snp/rs200950385/) |
| Variant type | single nucleotide variant |
| Location | chr11:72302331-72302331 (GRCh38) |
| ClinVar | [VCV724996](https://www.ncbi.nlm.nih.gov/clinvar/variation/724996/) |

**All HGVS expressions:** `LRG_1338:g.137354C>T`, `LRG_1338t1:c.1140C>T`, `NC_000011.10:g.72302331G>A`, `NC_000011.9:g.72013375G>A`, `NG_042130.2:g.137354C>T`, `NM_001258392.3:c.1140C>T`, `NM_001258393.3:c.1053C>T`, `NM_001258394.3:c.1095C>T`, `NM_030813.6:c.1230C>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 5.901, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.74**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.0038% · 7/60,018 in the highest group · 66/1,614,114 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0117% | 8,574 |
| European (non-Finnish) | 0.00458% | 21,852 |
| African / African-American | 0.004% | 25,007 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,251 |

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-12.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-16 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-04-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-27 |

## 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, not provided, CLPB-related disorder, not specified, AllHighlyPenetrant, CLPB-related condition, none provided, CLPB Deficiency, 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia.

### 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 724996). 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.*