SAMHD1

Chr 20ADAR

SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1

Also known as: CHBL2, DCIP, HDDC1, MOP-5, SBBI88, hSAMHD1

NCBI Gene: 25939 ENSG00000101347 UniProt: Q9Y3Z3 OMIM: 606754

The SAMHD1 protein functions as a deoxynucleoside triphosphatase that restricts viral replication by depleting cellular dNTP pools and regulates DNA replication fork stability. Mutations cause Aicardi-Goutières syndrome 5, an early-onset interferonopathy presenting with neurologic features, and chilblain lupus 2, with both autosomal recessive and autosomal dominant inheritance patterns reported. This gene is extremely intolerant to loss-of-function variants, indicating its critical cellular role.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome. [provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.942 OMIM phenotypes

Clinical Summary— SAMHD1

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Gene-Disease Validity (ClinGen)

SAMHD1-related type 1 interferonopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

163 unique Pathogenic / Likely Pathogenic· 357 VUS of 1040 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SAMHD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.86

OE 0.67 (0.49–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.55Z-score

OE missense 0.77 (0.69–0.85)

267 obs / 348.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.49–0.94)

0≤0.351.4

Missense OE?0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 25 / 37.2Missense obs/exp: 267 / 348.3Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSAMHD1-related Aicardi-Goutieres syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.6248th %ile

LOF

0.3067th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1040 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic95

Likely Pathogenic68

VUS357

Likely Benign440

Benign29

Conflicting31

Pathogenic

Likely Pathogenic

357

VUS

440

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	71	1	23	0	95
Likely Pathogenic	47	10	10	1	68
VUS	7	292	41	17	357
Likely Benign	1	4	189	246	440
Benign	2	0	25	2	29
Conflicting	—				31
Total	128	307	288	266	1,020

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap SAMHD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →