# NM_152281.3(GORAB):c.5del (p.Ala2fs)

https://sugi.bio/variant/gorab-p-ala2fs

## Summary

**GORAB p.Ala2fs (c.5del)** is classified **Pathogenic/Likely pathogenic** in GORAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). No gnomAD frequency available for this variant; Associated with geroderma osteodysplasticum.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1571232872 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GORAB gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to geroderma osteodysplasticum.

*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/0000413/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GORAB](https://sugi.bio/atlas/gene/GORAB/) |
| Protein change (HGVS p.) | p.Ala2fs |
| Coding change (HGVS c.) | c.5del |
| MANE Select transcript | [NM_152281](https://www.ncbi.nlm.nih.gov/nuccore/NM_152281) |
| dbSNP | [rs1571232872](https://www.ncbi.nlm.nih.gov/snp/rs1571232872/) |
| Variant type | Deletion |
| Location | chr1:170532228-170532228 (GRCh38) |
| ClinVar | [VCV804379](https://www.ncbi.nlm.nih.gov/clinvar/variation/804379/) |

**All HGVS expressions:** `NC_000001.10:g.170501369del`, `NC_000001.11:g.170532228del`, `NG_012237.1:g.5107del`, `NM_001146039.2:c.5del`, `NM_001320252.2:c.-761del`, `NM_152281.3:c.5del`, `NR_027397.2:n.63del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 9.596, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.802, pLI 0.0054121. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 5**, 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**GORAB** population constraint: LOEUF 0.802, pLI 0.0054121, missense-Z 0.29956; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **geroderma osteodysplastica** — Definitive (AR)

## Protein context {#protein}

Residue **2** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 71.86, 38% of residues very-high.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-10.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Hadassah Hebrew University Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-06-20 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[geroderma osteodysplasticum](https://sugi.bio/atlas/disease/geroderma-osteodysplasticum/).

**Reported phenotype names (ClinVar):** Geroderma osteodysplastica, WALT DISNEY DWARFISM.

## Similar variants {#similar}

Related GORAB variant pages (same residue, condition, or type): [GORAB p.Lys137fs](/variant/gorab-p-lys137fs), [GORAB p.Pro86fs](/variant/gorab-p-pro86fs), [GORAB p.Ser335fs](/variant/gorab-p-ser335fs), [GORAB p.Gly96fs](/variant/gorab-p-gly96fs), [GORAB p.Arg262Ter](/variant/gorab-p-arg262ter), [GORAB p.Arg35Ter](/variant/gorab-p-arg35ter), [GORAB p.Arg40Ter](/variant/gorab-p-arg40ter), [GORAB p.Gln64Ter](/variant/gorab-p-gln64ter).

### 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 804379). 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.*