# NM_144573.4(NEXN):c.732C>A (p.Pro244=)

https://sugi.bio/variant/nexn-p-pro244

## Summary

**NEXN p.Pro244= (c.732C>A)** is classified **Benign/Likely benign** in NEXN (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0655%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs201171783 · 13 submitters · 4 linked conditions · ultra-rare (popmax 0.0655%, nfe)

## For patients & families {#patients}

This is a change in the NEXN gene that is classified as benign/likely benign — not considered disease-causing, submitted by 13 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.Pro244= |
| Coding change (HGVS c.) | c.732C>A |
| MANE Select transcript | [NM_144573](https://www.ncbi.nlm.nih.gov/nuccore/NM_144573) |
| dbSNP | [rs201171783](https://www.ncbi.nlm.nih.gov/snp/rs201171783/) |
| Variant type | single nucleotide variant |
| Location | chr1:77926760-77926760 (GRCh38) |
| ClinVar | [VCV47910](https://www.ncbi.nlm.nih.gov/clinvar/variation/47910/) |

**All HGVS expressions:** `LRG_442:g.43246C>A`, `LRG_442t1:c.732C>A`, `NC_000001.10:g.78392445C>A`, `NC_000001.11:g.77926760C>A`, `NG_016625.1:g.43246C>A`, `NM_001172309.2:c.540C>A`, `NM_144573.4:c.732C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.437, GERP 0.928, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.66**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.30**, donor gain **0.00**.
- Pangolin: Δ**0.29** (gain), gain 0.29 / loss 0.02. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0655%** (nfe) · FAF95 0.0617% · FAF99 0.0601% · 773/1,179,922 in the highest group · 1,020/1,613,402 alleles overall — ultra-rare (popmax 0.0655%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.635% | 157 |
| European (non-Finnish) (grpmax) | 0.0655% | 1,526 |
| Remaining individuals (not grpmax-eligible) | 0.0608% | 1,644 |
| Finnish (not grpmax-eligible) | 0.0125% | 7,993 |
| African / African-American | 0.00937% | 10,676 |
| Admixed American | 0.00835% | 11,981 |
| East Asian | 0.00223% | 44,850 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (7 Likely benign, 6 Benign).

**Submission history:** 13 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-10-03 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-12-17 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-03 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Benign | criteria provided, single submitter | clinical testing | 2017-10-31 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2023-12-10 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-04-28 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-03-27 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [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 specified, Dilated cardiomyopathy 1CC, Hypertrophic cardiomyopathy 20, Cardiomyopathy, not provided, NEXN-related disorder, NEXN-related condition, NEXN-related disorders, AllHighlyPenetrant.

## Similar variants {#similar}

Related NEXN variant pages (same residue, condition, or type): [NEXN p.Pro244Ser](/variant/nexn-p-pro244ser), [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.865-4T>C](/variant/nexn-c-865-minus-4t-c), [NEXN c.-10T>C](/variant/nexn-c-minus-10t-c).

### 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 47910). 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.*