# NM_144573.4(NEXN):c.450T>A (p.Ile150=)

https://sugi.bio/variant/nexn-p-ile150

## Summary

**NEXN p.Ile150= (c.450T>A)** is classified **Conflicting classifications of pathogenicity** in NEXN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). Very rare (popmax 0.000172%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1064797051 · 3 submitters · 3 linked conditions · very rare (popmax 0.000172%, nfe)

## For patients & families {#patients}

This is a change in the NEXN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Cardiovascular phenotype.

*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 | [NEXN](https://sugi.bio/atlas/gene/NEXN/) |
| Protein change (HGVS p.) | p.Ile150= |
| Coding change (HGVS c.) | c.450T>A |
| MANE Select transcript | [NM_144573](https://www.ncbi.nlm.nih.gov/nuccore/NM_144573) |
| dbSNP | [rs1064797051](https://www.ncbi.nlm.nih.gov/snp/rs1064797051/) |
| Variant type | single nucleotide variant |
| Location | chr1:77925190-77925190 (GRCh38) |
| ClinVar | [VCV424583](https://www.ncbi.nlm.nih.gov/clinvar/variation/424583/) |

**All HGVS expressions:** `LRG_442:g.41676T>A`, `LRG_442t1:c.450T>A`, `NC_000001.10:g.78390875T>A`, `NC_000001.11:g.77925190T>A`, `NG_016625.1:g.41676T>A`, `NM_001172309.2:c.258T>A`, `NM_144573.4:c.450T>A`

## 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 5.055, GERP 2.14, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.33**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.28 acceptor 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 **0.000172%** (nfe) · FAF95 2.9e-05% · FAF99 1.1e-05% · 2/1,163,952 in the highest group · 2/1,593,932 alleles overall — very rare (popmax 0.000172%, 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}

**NEXN** population constraint: LOEUF 0.878, pLI 1.3677e-13, missense-Z 0.4651. *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):

- **hypertrophic cardiomyopathy** — Limited (AD)
- **dilated cardiomyopathy 1CC** — Strong (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.78, 20% of residues very-high.

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

*Describes the biological roles of NEXN (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:** NEXN's established molecular role includes structural constituent of muscle.


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

**Molecular function:** structural constituent of muscle, actin filament binding.

**Biological process:** regulation of cell migration, regulation of cytoskeleton organization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-06.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-03 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-06 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [dilated cardiomyopathy 1CC](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1cc/), [hypertrophic cardiomyopathy 20](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-20/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Dilated cardiomyopathy 1CC, Hypertrophic cardiomyopathy 20, none provided.

## Similar variants {#similar}

Related NEXN variant pages (same residue, condition, or type): [NEXN p.Gly100Ter](/variant/nexn-p-gly100ter), [NEXN c.1473+1G>T](/variant/nexn-c-1473-plus-1g-t), [NEXN c.219+5T>G](/variant/nexn-c-219-plus-5t-g), [NEXN c.299-3T>C](/variant/nexn-c-299-minus-3t-c), [NEXN c.448-4A>G](/variant/nexn-c-448-minus-4a-g), [NEXN c.-10T>C](/variant/nexn-c-minus-10t-c), [NEXN p.Ala266Gly](/variant/nexn-p-ala266gly), [NEXN p.Ala343Val](/variant/nexn-p-ala343val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 424583). 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.*