# NM_015474.4(SAMHD1):c.888C>T (p.Phe296=)

https://sugi.bio/variant/samhd1-p-phe296

## Summary

**SAMHD1 p.Phe296= (c.888C>T)** is classified **Uncertain significance** in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-21). Very rare (popmax 0.00223%, eas); Associated with Aicardi-Goutieres syndrome 5.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs541385940 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the SAMHD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Aicardi-Goutieres syndrome 5.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | SAMHD1 is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Aicardi-Goutières syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Spasticity — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Hypertonia — Very frequent (99-80%)
- Porencephaly — Very frequent (99-80%)
- Arrhinencephaly — Very frequent (99-80%)
- Intellectual disability, profound — Very frequent (99-80%)
- Multifocal cerebral white matter abnormalities — Very frequent (99-80%)
- Convex nasal ridge — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010151/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SAMHD1](https://sugi.bio/atlas/gene/SAMHD1/) |
| Protein change (HGVS p.) | p.Phe296= |
| Coding change (HGVS c.) | c.888C>T |
| MANE Select transcript | [NM_015474](https://www.ncbi.nlm.nih.gov/nuccore/NM_015474) |
| dbSNP | [rs541385940](https://www.ncbi.nlm.nih.gov/snp/rs541385940/) |
| Variant type | single nucleotide variant |
| Location | chr20:36917014-36917014 (GRCh38) |
| ClinVar | [VCV2174788](https://www.ncbi.nlm.nih.gov/clinvar/variation/2174788/) |

**All HGVS expressions:** `LRG_281:g.39830C>T`, `LRG_281t1:c.888C>T`, `NC_000020.10:g.35545417G>A`, `NC_000020.11:g.36917014G>A`, `NG_017059.1:g.39830C>T`, `NM_001363729.2:c.888C>T`, `NM_001363733.2:c.888C>T`, `NM_015474.4:c.888C>T`

## 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 loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.929, GERP -0.12, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.159**. 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 **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,860 in the highest group · 1/152,260 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**SAMHD1** population constraint: LOEUF 0.889, pLI 2.4032e-07, missense-Z 1.5222; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **SAMHD1-related type 1 interferonopathy** — Definitive (AR)

## Protein context {#protein}

Residue **296** lies in an α-helix; the hd domain.

AlphaFold model confidence (whole protein): pLDDT 88.45, 75% of residues very-high.

**76 experimental structure(s)** (PDB): [2E8O](https://www.rcsb.org/structure/2E8O), [3U1N](https://www.rcsb.org/structure/3U1N), [4BZB](https://www.rcsb.org/structure/4BZB), [4BZC](https://www.rcsb.org/structure/4BZC), [4CC9](https://www.rcsb.org/structure/4CC9), [4MZ7](https://www.rcsb.org/structure/4MZ7) — incl. mutant structure 4BZB.

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

*Describes the biological roles of SAMHD1 (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:** SAMHD1's established molecular role includes nucleic acid binding. p.Phe296= falls in the hd domain.


### Pathways affected {#pathways}

SAMHD1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [Nucleotide catabolism](https://reactome.org/content/detail/R-HSA-8956319) | curated |

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

**Molecular function:** nucleic acid binding, single-stranded DNA binding, RNA binding, RNA nuclease activity, zinc ion binding, dGTPase activity.

**Biological process:** double-strand break repair via homologous recombination, dGTP catabolic process, DNA damage response, deoxyribonucleotide catabolic process, regulation of innate immune response, dATP catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-21.

**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 | 2022-04-21 |

## Associated conditions {#conditions}

[Aicardi-Goutieres syndrome 5](https://sugi.bio/atlas/disease/aicardi-goutieres-syndrome-5/).

**Reported phenotype names (ClinVar):** Aicardi-Goutieres syndrome 5.

## Similar variants {#similar}

Related SAMHD1 variant pages (same residue, condition, or type): [SAMHD1 c.1062+1G>T](/variant/samhd1-c-1062-plus-1g-t), [SAMHD1 c.1411-2A>G](/variant/samhd1-c-1411-minus-2a-g), [SAMHD1 c.509+1G>A](/variant/samhd1-c-509-plus-1g-a), [SAMHD1 c.626-1G>C](/variant/samhd1-c-626-minus-1g-c), [SAMHD1 p.Arg106Ter](/variant/samhd1-p-arg106ter), [SAMHD1 p.Arg134Ter](/variant/samhd1-p-arg134ter), [SAMHD1 p.Arg143Cys](/variant/samhd1-p-arg143cys), [SAMHD1 p.Arg143His](/variant/samhd1-p-arg143his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2174788). 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.*