# NM_001164508.2(NEB):c.24071C>G (p.Pro8024Arg)

https://sugi.bio/variant/neb-p-pro8024arg

## Summary

**NEB p.Pro8024Arg (c.24071C>G)** is classified **Uncertain significance** in NEB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). Very rare (popmax 0.0012%, sas); Associated with nemaline myopathy 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2153021543 · 1 submitter · 1 linked condition · very rare (popmax 0.0012%, sas)

## For patients & families {#patients}

This is a change in the NEB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to nemaline myopathy 2.

*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) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | NEB is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Severe congenital nemaline myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Breech presentation — Frequent (79-30%)
- Dysphagia — Frequent (79-30%)
- Respiratory distress — Frequent (79-30%)
- Hypokinesia — Frequent (79-30%)
- Respiratory failure — Frequent (79-30%)
- Skeletal muscle atrophy — Frequent (79-30%)
- Axial muscle weakness — Frequent (79-30%)
- Nemaline bodies — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015209/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NEB](https://sugi.bio/atlas/gene/NEB/) |
| Protein change (HGVS p.) | p.Pro8024Arg |
| Coding change (HGVS c.) | c.24071C>G |
| MANE Select transcript | [NM_001164508](https://www.ncbi.nlm.nih.gov/nuccore/NM_001164508) |
| dbSNP | [rs2153021543](https://www.ncbi.nlm.nih.gov/snp/rs2153021543/) |
| Variant type | single nucleotide variant |
| Location | chr2:151499341-151499341 (GRCh38) |
| ClinVar | [VCV1471982](https://www.ncbi.nlm.nih.gov/clinvar/variation/1471982/) |

**All HGVS expressions:** `LRG_202:g.240147C>G`, `NC_000002.11:g.152355855G>C`, `NC_000002.12:g.151499341G>C`, `NG_009382.2:g.240147C>G`, `NM_001164507.2:c.24071C>G`, `NM_001164508.2:c.24071C>G`, `NM_001271208.2:c.24176C>G`, `NM_004543.5:c.18826-2973C>G`

## 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 11.85, GERP 2.07, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 25.2**. 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 0.92** across the covering region of the MANE Select transcript (151,485,763–151,576,354), spanning 90,591 bp. Chi-square p 4.4e-06. 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, Δ0.26 acceptor loss), 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 **0.0012%** (sas) · 1/83,660 in the highest group · 1/1,393,224 alleles overall — very rare (popmax 0.0012%, sas).

*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}

**NEB** population constraint: LOEUF 0.597, pLI 5.309e-52, missense-Z 2.2497. *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):

- **nemaline myopathy 2** — Definitive (AR)
- **autosomal dominant nebulin-related myopathy** — Moderate (AD)

## Protein context {#protein}

Residue **8024** lies in a UniProt-annotated variant site (in amc6).

**3 experimental structure(s)** (PDB): [1ARK](https://www.rcsb.org/structure/1ARK), [1NEB](https://www.rcsb.org/structure/1NEB), [6Y17](https://www.rcsb.org/structure/6Y17).

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

*Describes the biological roles of NEB (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-23.

**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 | 2023-05-23 |

## Associated conditions {#conditions}

[nemaline myopathy 2](https://sugi.bio/atlas/disease/nemaline-myopathy-2/).

**Reported phenotype names (ClinVar):** Nemaline myopathy 2, Nemaline myopathy 2, autosomal recessive.

## Similar variants {#similar}

Related NEB variant pages (same residue, condition, or type): [NEB c.11910+1G>A](/variant/neb-c-11910-plus-1g-a), [NEB c.6076-1G>T](/variant/neb-c-6076-minus-1g-t), [NEB c.78+1G>A](/variant/neb-c-78-plus-1g-a), [NEB p.Arg2313Ter](/variant/neb-p-arg2313ter), [NEB p.Asp498Gly](/variant/neb-p-asp498gly), [NEB p.Ser6366Ile](/variant/neb-p-ser6366ile), [NEB p.Ser6648=](/variant/neb-p-ser6648), [NEB c.22590+2T>C](/variant/neb-c-22590-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1471982). 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.*