# NM_006364.4(SEC23A):c.129del (p.Pro44fs)

https://sugi.bio/variant/sec23a-p-pro44fs

## Summary

**SEC23A p.Pro44fs (c.129del)** is classified **Uncertain significance** in SEC23A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). Associated with craniolenticulosutural dysplasia.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SEC23A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to craniolenticulosutural dysplasia.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016647/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SEC23A](https://sugi.bio/atlas/gene/SEC23A/) |
| Protein change (HGVS p.) | p.Pro44fs |
| Coding change (HGVS c.) | c.129del |
| MANE Select transcript | [NM_006364](https://www.ncbi.nlm.nih.gov/nuccore/NM_006364) |
| Variant type | Deletion |
| Location | chr14:39095990-39095990 (GRCh38) |
| ClinVar | [VCV4729181](https://www.ncbi.nlm.nih.gov/clinvar/variation/4729181/) |

**All HGVS expressions:** `NC_000014.8:g.39565194del`, `NC_000014.9:g.39095990del`, `NG_012157.1:g.12244del`, `NM_006364.4:c.129del`

## 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 9.803, GERP 1.9, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.708, pLI 1.8029e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 20**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**SEC23A** population constraint: LOEUF 0.708, pLI 1.8029e-05, missense-Z 2.0263. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.86, 85% of residues very-high.

**38 experimental structure(s)** (PDB): [2NUP](https://www.rcsb.org/structure/2NUP), [2NUT](https://www.rcsb.org/structure/2NUT), [2YRC](https://www.rcsb.org/structure/2YRC), [2YRD](https://www.rcsb.org/structure/2YRD), [3EFO](https://www.rcsb.org/structure/3EFO), [3EG9](https://www.rcsb.org/structure/3EG9) — incl. mutant structure 2YRD.

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

*Describes the biological roles of SEC23A (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:** SEC23A's established molecular role includes zinc ion binding. In Reactome, SEC23A is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** SEC23A loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

SEC23A participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Antigen Presentation: Folding, assembly and peptide loading of class I MHC](https://reactome.org/content/detail/R-HSA-983170) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Regulation of cholesterol biosynthesis by SREBP (SREBF)](https://reactome.org/content/detail/R-HSA-1655829) | electronic |

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

**Molecular function:** zinc ion binding.

**Biological process:** COPII-coated vesicle cargo loading.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-17.

**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 | 2025-10-17 |

## Associated conditions {#conditions}

[craniolenticulosutural dysplasia](https://sugi.bio/atlas/disease/craniolenticulosutural-dysplasia/).

**Reported phenotype names (ClinVar):** Craniolenticulosutural dysplasia, BOYADJIEV-JABS SYNDROME.

## Similar variants {#similar}

Related SEC23A variant pages (same residue, condition, or type): [SEC23A p.Asp50_Pro52del](/variant/sec23a-p-asp50-pro52del), [SEC23A p.Asp754fs](/variant/sec23a-p-asp754fs), [SEC23A p.Leu60fs](/variant/sec23a-p-leu60fs), [SEC23A p.Pro565fs](/variant/sec23a-p-pro565fs), [SEC23A p.Ala284Pro](/variant/sec23a-p-ala284pro), [SEC23A p.Ala478Ser](/variant/sec23a-p-ala478ser), [SEC23A p.Arg123Cys](/variant/sec23a-p-arg123cys), [SEC23A p.Arg476His](/variant/sec23a-p-arg476his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4729181). 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.*