Is SAMHD1 p.Glu83Asp (c.249G>T) pathogenic?

SAMHD1 p.Glu83Asp (c.249G>T) is classified Uncertain significance in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-06). AlphaMissense: likely benign (0.1605); Very rare (popmax 8.48e-05%, nfe); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Glu83Asp (c.249G>T)?

SAMHD1 p.Glu83Asp (c.249G>T) is associated with Aicardi-Goutieres syndrome 5 (ClinVar).

How common is SAMHD1 p.Glu83Asp (c.249G>T) in the general population?

SAMHD1 p.Glu83Asp (c.249G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

What do computational predictors say about SAMHD1 p.Glu83Asp (c.249G>T)?

AlphaMissense predicts likely benign (score 0.1605) — an in-silico prediction, not a clinical call.

SAMHD1 p.Glu83Asp

c.249G>T · rs2063689102 · VCV838234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 5

Computational evidence

Protein change
AlphaMissense	0.1605	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -3.1
Regional constraint	o/e 0.85	unconstrained · MANE · 59 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	12.82	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,368 alleles

Overall 6.85e-05% 1/1,460,874 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.Glu83Asp
Coding: c.249G>T
MANE Select: NM_015474
dbSNP: rs2063689102
Type: single nucleotide variant
Location: chr20:36946764 (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 83: the sam domain; 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

For Aicardi-Goutières syndrome (Orphanet):

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

Similar variants

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
SAMHD1 p.Arg143His 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-glu83asp (accessed [today's date]).

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