Is SAMHD1 p.Pro581= (c.1743G>A) pathogenic?

SAMHD1 p.Pro581= (c.1743G>A) is classified Conflicting classifications of pathogenicity in SAMHD1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-31). Ultra-rare (popmax 0.0495%, mid); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Pro581= (c.1743G>A)?

SAMHD1 p.Pro581= (c.1743G>A) is associated with Aicardi-Goutieres syndrome 5, Aicardi-Goutieres syndrome (ClinVar).

How common is SAMHD1 p.Pro581= (c.1743G>A) in the general population?

SAMHD1 p.Pro581= (c.1743G>A) is ultra-rare (popmax 0.0495%, mid) (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.Pro581=

c.1743G>A · rs374642075 · VCV741733

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

Aicardi-Goutieres syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -2.6
Overall
CADD	0.498	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.0075% 121/1,614,166 alleles · ultra-rare exomes 110/1,461,884 · genomes 11/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
South Asian	0.0154%	6,506
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.0117%	8,572
European (non-Finnish)	0.0072%	13,883
Finnishnot grpmax-eligible	0.00469%	21,344

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.Pro581=
Coding: c.1743G>A
MANE Select: NM_015474
dbSNP: rs374642075
Type: single nucleotide variant
Location: chr20:36897825 (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 581: a UniProt-annotated variant site (in ags5; does not affect dntp regulation, while affecting ability to promote dna end resection at stalled replication forks); an α-helix

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

Also linked: Aicardi-Goutieres syndrome

For Aicardi-Goutières syndrome (Orphanet):

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

Similar variants

SAMHD1 p.Pro581Leu Uncertain significance ★ ⚠ same residue
SAMHD1 c.1062+1G>T Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 c.1411-2A>G Pathogenic ★★ same condition
SAMHD1 c.509+1G>A Likely pathogenic ★★ same condition
SAMHD1 c.626-1G>C Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Arg106Ter Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Arg134Ter Pathogenic/Likely pathogenic ★★ same condition
SAMHD1 p.Arg143Cys 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-pro581 (accessed [today's date]).

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