Is SAMHD1 p.Ser247Phe (c.740C>T) pathogenic?

SAMHD1 p.Ser247Phe (c.740C>T) is classified Uncertain significance in SAMHD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.2591); Very rare (popmax 6.2e-05%); Associated with Aicardi-Goutieres syndrome.

What condition is associated with SAMHD1 p.Ser247Phe (c.740C>T)?

SAMHD1 p.Ser247Phe (c.740C>T) is associated with Aicardi-Goutieres syndrome (ClinVar).

How common is SAMHD1 p.Ser247Phe (c.740C>T) in the general population?

SAMHD1 p.Ser247Phe (c.740C>T) is very rare (popmax 6.2e-05%) (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.Ser247Phe (c.740C>T)?

AlphaMissense predicts likely benign (score 0.2591) — an in-silico prediction, not a clinical call.

SAMHD1 p.Ser247Phe

c.740C>T · VCV4061226

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Aicardi-Goutieres syndrome

Computational evidence

Protein change
AlphaMissense	0.2591	likely benign
REVEL	0.591	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.3	GERP 1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 59 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	24.6	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 6.2e-05%

Overall 6.2e-05% 1/1,613,526 alleles · very rare exomes 1/1,461,322 · genomes 0/152,204 · joint denominator

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.Ser247Phe
Coding: c.740C>T
MANE Select: NM_015474
Type: single nucleotide variant
Location: chr20:36919476 (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 247: an α-helix; the hd domain

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

Disease context

Aicardi-Goutieres syndrome — 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.Ser247= Likely benign ★ same residue
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.Arg145Ter Pathogenic ★★ same condition
SAMHD1 p.Arg164Ter 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-ser247phe (accessed [today's date]).

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