Is SAMHD1 p.Ser538fs (c.1612del) pathogenic?

SAMHD1 p.Ser538fs (c.1612del) is classified Pathogenic in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). Very rare (popmax 0.00133%, afr); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Ser538fs (c.1612del)?

SAMHD1 p.Ser538fs (c.1612del) is associated with Aicardi-Goutieres syndrome 5 (ClinVar).

How common is SAMHD1 p.Ser538fs (c.1612del) in the general population?

SAMHD1 p.Ser538fs (c.1612del) is very rare (popmax 0.00133%, afr) (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.Ser538fs

c.1612del · rs2515217684 · VCV2838205

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 15 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,032 alleles

Overall 6.84e-05% 1/1,461,844 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.Ser538fs
Coding: c.1612del
MANE Select: NM_015474
dbSNP: rs2515217684
Type: Deletion
Location: chr20:36897956 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.45 · 76 PDB

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 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
SAMHD1 p.Met216fs Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Met505fs 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-ser538fs (accessed [today's date]).

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