# NM_080424.4(SP110):c.1493_1494insCAAC (p.Pro499fs)

https://sugi.bio/variant/sp110-p-pro499fs

## Summary

**SP110 p.Pro499fs (c.1493_1494insCAAC)** is classified **Pathogenic** in SP110 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). Very rare (popmax 0.000169%, nfe); Associated with hepatic veno-occlusive disease-immunodeficiency syndrome.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the SP110 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hepatic veno-occlusive disease-immunodeficiency syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | SP110 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Hepatic veno-occlusive disease-immunodeficiency syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal circulating interleukin concentration — Very frequent (99-80%)
- Panhypogammaglobulinemia — Very frequent (99-80%)
- Abnormal serum interferon-gamma level — Very frequent (99-80%)
- Abnormal lymphocyte count — Very frequent (99-80%)
- Decreased total T cell count — Frequent (79-30%)
- Cough — Frequent (79-30%)
- Decreased proportion of memory B cells — Frequent (79-30%)
- Recurrent gastroenteritis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010083/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SP110](https://sugi.bio/atlas/gene/SP110/) |
| Protein change (HGVS p.) | p.Pro499fs |
| Coding change (HGVS c.) | c.1493_1494insCAAC |
| MANE Select transcript | [NM_080424](https://www.ncbi.nlm.nih.gov/nuccore/NM_080424) |
| Variant type | Insertion |
| Location | chr2:230177634-230177635 (GRCh38) |
| ClinVar | [VCV4714257](https://www.ncbi.nlm.nih.gov/clinvar/variation/4714257/) |

**All HGVS expressions:** `LRG_109:g.47477_47478insCAAC`, `LRG_109t1:c.1490_1491insAACC`, `NC_000002.11:g.231042353_231042354insGGTT`, `NC_000002.12:g.230177637_230177638insGGTT`, `NG_008295.1:g.47477_47478insCAAC`, `NM_001185015.2:c.1511_1512insCAAC`, `NM_001378442.1:c.1511_1512insCAAC`, `NM_001378443.1:c.1493_1494insCAAC`, `NM_001378444.1:c.1511_1512insCAAC`, `NM_001378445.1:c.1511_1512insCAAC`, `NM_001378446.1:c.1511_1512insCAAC`, `NM_001378447.1:c.1343_1344insCAAC`, `NM_004509.5:c.1493_1494insCAAC`, `NM_004510.4:c.1493_1494insCAAC`, `NM_080424.4:c.1493_1494insCAAC`

## 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 -10.608, GERP -3.88 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.826, pLI 2.8523e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 19**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,000 in the highest group · 2/1,614,186 alleles overall — very rare (popmax 0.000169%, 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}

**SP110** population constraint: LOEUF 0.826, pLI 2.8523e-07, missense-Z 1.5861. *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):

- **hepatic veno-occlusive disease-immunodeficiency syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **499** lies in the sand domain.

AlphaFold model confidence (whole protein): pLDDT 58.63, 16% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-30 |

## Associated conditions {#conditions}

[hepatic veno-occlusive disease-immunodeficiency syndrome](https://sugi.bio/atlas/disease/hepatic-veno-occlusive-disease-immunodeficiency-syndrome/).

**Reported phenotype names (ClinVar):** Hepatic veno-occlusive disease-immunodeficiency syndrome, Hepatic Veno-Occlusive Disease with Immunodeficiency.

## Similar variants {#similar}

Related SP110 variant pages (same residue, condition, or type): [SP110 c.1888-2A>G](/variant/sp110-c-1888-minus-2a-g), [SP110 p.Arg344Ter](/variant/sp110-p-arg344ter), [SP110 p.Arg373fs](/variant/sp110-p-arg373fs), [SP110 p.Arg421Ter](/variant/sp110-p-arg421ter), [SP110 p.Arg448Ter](/variant/sp110-p-arg448ter), [SP110 p.Arg554Ter](/variant/sp110-p-arg554ter), [SP110 p.Arg631Ter](/variant/sp110-p-arg631ter), [SP110 p.Asp455Ter](/variant/sp110-p-asp455ter).

### 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 4714257). 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.*