# NM_015474.4(SAMHD1):c.120C>T (p.Pro40=)

https://sugi.bio/variant/samhd1-p-pro40

## Summary

**SAMHD1 p.Pro40= (c.120C>T)** is classified **Likely benign** in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-02). Very rare (popmax 0.000169%, nfe); Associated with Aicardi-Goutieres syndrome 5.

**At a glance:** Likely benign · review: Single submitter · rsID rs1164431300 · 1 submitter · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the SAMHD1 gene that is classified as likely benign — not considered disease-causing, 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.Pro40= |
| Coding change (HGVS c.) | c.120C>T |
| MANE Select transcript | [NM_015474](https://www.ncbi.nlm.nih.gov/nuccore/NM_015474) |
| dbSNP | [rs1164431300](https://www.ncbi.nlm.nih.gov/snp/rs1164431300/) |
| Variant type | single nucleotide variant |
| Location | chr20:36951524-36951524 (GRCh38) |
| ClinVar | [VCV1127103](https://www.ncbi.nlm.nih.gov/clinvar/variation/1127103/) |

**All HGVS expressions:** `LRG_281:g.5320C>T`, `NC_000020.10:g.35579927G>A`, `NC_000020.11:g.36951524G>A`, `NG_017059.1:g.5320C>T`, `NM_001363729.2:c.120C>T`, `NM_001363733.2:c.120C>T`, `NM_015474.4:c.120C>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.251, GERP -3.22 — fast-evolving / accelerated position
- CADD: **PHRED 0.683**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,022 in the highest group · 2/1,614,084 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}

**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}


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.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-02 |

## 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 p.Pro40Leu](/variant/samhd1-p-pro40leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1127103). 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.*