Is SAMHD1 p.Ser23fs (c.66del) pathogenic?

SAMHD1 p.Ser23fs (c.66del) is classified Pathogenic in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). Very rare (popmax 0.000339%, nfe); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Ser23fs (c.66del)?

SAMHD1 p.Ser23fs (c.66del) is associated with Aicardi-Goutieres syndrome 5 (ClinVar).

How common is SAMHD1 p.Ser23fs (c.66del) in the general population?

SAMHD1 p.Ser23fs (c.66del) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SAMHD1 p.Ser23fs

c.66del · rs1442728513 · VCV858736

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Aicardi-Goutieres syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.65, phastCons 1
Overall
CADD	19.51	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,970 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,922 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SAMHD1
Protein: p.Ser23fs
Coding: c.66del
MANE Select: NM_015474
dbSNP: rs1442728513
Type: Deletion
Location: chr20:36951578 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.45 · 76 PDB
Residue 23: the 'disordered' region

Full SAMHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aicardi-Goutières syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SAMHD1 p.Ser23Ter Pathogenic/Likely pathogenic ★★ same residue
SAMHD1 p.Ser23Thr Uncertain significance ★ ⚠ same residue
SAMHD1 c.349-6_354del Likely pathogenic ★★ same condition
SAMHD1 p.Ala529fs Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Gln190fs Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Glu479fs Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Ile222fs Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Lys492fs Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/samhd1-p-ser23fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown