# NM_170707.4(LMNA):c.76A>G (p.Ile26Val)

https://sugi.bio/variant/lmna-p-ile26val

## Summary

**LMNA p.Ile26Val (c.76A>G)** is classified **Uncertain significance** in LMNA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: likely pathogenic (0.6794); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1302425397 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the LMNA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012431/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LMNA](https://sugi.bio/atlas/gene/LMNA/) |
| Protein change (HGVS p.) | p.Ile26Val |
| Coding change (HGVS c.) | c.76A>G |
| MANE Select transcript | [NM_170707](https://www.ncbi.nlm.nih.gov/nuccore/NM_170707) |
| dbSNP | [rs1302425397](https://www.ncbi.nlm.nih.gov/snp/rs1302425397/) |
| Variant type | single nucleotide variant |
| Location | chr1:156114994-156114994 (GRCh38) |
| ClinVar | [VCV1720742](https://www.ncbi.nlm.nih.gov/clinvar/variation/1720742/) |

**All HGVS expressions:** `LRG_254:g.37422A>G`, `LRG_254t1:c.76A>G`, `LRG_254t2:c.76A>G`, `LRG_254t3:c.76A>G`, `NC_000001.10:g.156084785A>G`, `NC_000001.11:g.156114994A>G`, `NG_008692.2:g.37422A>G`, `NM_001282625.2:c.76A>G`, `NM_001282626.2:c.76A>G`, `NM_001406983.1:c.76A>G`, `NM_001406984.1:c.76A>G`, `NM_001406985.1:c.76A>G`, `NM_001406986.1:c.-348A>G`, `NM_001406990.1:c.-326A>G`, `NM_001406991.1:c.76A>G`, `NM_001406992.1:c.76A>G`, `NM_001406994.1:c.-589A>G`, `NM_001406995.1:c.-326A>G`, `NM_001406999.1:c.-769A>G`, `NM_001407000.1:c.-589A>G`, `NM_001407001.1:c.-432A>G`, `NM_001407002.1:c.-326A>G`, `NM_005572.4:c.76A>G`, `NM_170707.4:c.76A>G`, `NM_170708.4:c.76A>G`, `NR_047544.1:n.717A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6794)
- REVEL 0.295 (indeterminate)
- SaProt LLR -6.026 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 11.051, GERP 1.32, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.0**. 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 0.60** across the covering region of the MANE Select transcript (156,114,919–156,135,909), spanning 20,990 bp. Chi-square p 3e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**LMNA** population constraint: LOEUF 0.412, pLI 0.99995, missense-Z 3.1003; ClinGen dosage — haploinsufficiency 3, 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):

- **dilated cardiomyopathy 1A** — Definitive (AD)
- **lipodystrophy** — Definitive (SD)
- **arrhythmogenic right ventricular cardiomyopathy** — Limited (AD)

## Protein context {#protein}

Residue **26** lies in a β-strand; the 'interaction with mlip' region; the 'head' region.

AlphaFold model confidence (whole protein): pLDDT 77.55, 60% of residues very-high.

**28 experimental structure(s)** (PDB): [1IFR](https://www.rcsb.org/structure/1IFR), [1IVT](https://www.rcsb.org/structure/1IVT), [1X8Y](https://www.rcsb.org/structure/1X8Y), [2XV5](https://www.rcsb.org/structure/2XV5), [2YPT](https://www.rcsb.org/structure/2YPT), [3GEF](https://www.rcsb.org/structure/3GEF) — incl. mutant structure 2YPT.

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

*Describes the biological roles of LMNA (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:** LMNA's established molecular role includes structural constituent of cytoskeleton. p.Ile26Val falls in the interaction with mlip region. In Reactome, LMNA is annotated in disease pathway(s) including **Signaling by BRAF and RAF1 fusions**, **Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models**.

**Disease mechanism (Reactome):** LMNA loss or alteration is curated in [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803).

### Pathways affected {#pathways}

LMNA participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803) | other |
| [XBP1(S) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381038) | curated |
| [Breakdown of the nuclear lamina](https://reactome.org/content/detail/R-HSA-352238) | other |
| [Depolymerization of the Nuclear Lamina](https://reactome.org/content/detail/R-HSA-4419969) | other |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | other |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | other |
| [Nuclear Envelope Breakdown](https://reactome.org/content/detail/R-HSA-2980766) | other |

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

**Molecular function:** structural constituent of cytoskeleton, identical protein binding, structural constituent of nuclear lamina.

**Biological process:** double-strand break repair via nonhomologous end joining, nuclear envelope organization, muscle organ development, intracellular protein localization, negative regulation of cell population proliferation, regulation of telomere maintenance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-03.

**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 | 2022-11-03 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 2](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth type 2.

## Same-residue context {#hotspot}

Residue **26** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [LMNA p.Ile26fs](/variant/lmna-p-ile26fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LMNA variant pages (same residue, condition, or type): [LMNA p.Ile26=](/variant/lmna-p-ile26), [LMNA p.Ile26Thr](/variant/lmna-p-ile26thr), [LMNA p.Ile26Leu](/variant/lmna-p-ile26leu), [LMNA c.1157+1G>A](/variant/lmna-c-1157-plus-1g-a), [LMNA c.1157+1G>T](/variant/lmna-c-1157-plus-1g-t), [LMNA c.1380+1G>A](/variant/lmna-c-1380-plus-1g-a), [LMNA c.1489-2A>G](/variant/lmna-c-1489-minus-2a-g), [LMNA c.1608+1G>A](/variant/lmna-c-1608-plus-1g-a).

### 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 1720742). 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.*