Is SAMHD1 p.Val502Phe (c.1504G>T) pathogenic?

SAMHD1 p.Val502Phe (c.1504G>T) is classified Uncertain significance in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.4712); Very rare (popmax 8.5e-05%, nfe); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Val502Phe (c.1504G>T)?

SAMHD1 p.Val502Phe (c.1504G>T) is associated with Aicardi-Goutieres syndrome 5 (ClinVar).

How common is SAMHD1 p.Val502Phe (c.1504G>T) in the general population?

SAMHD1 p.Val502Phe (c.1504G>T) is very rare (popmax 8.5e-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.Val502Phe (c.1504G>T)?

AlphaMissense predicts ambiguous (score 0.4712) — an in-silico prediction, not a clinical call.

SAMHD1 p.Val502Phe

c.1504G>T · VCV3688946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Aicardi-Goutieres syndrome 5

Computational evidence

Protein change
AlphaMissense	0.4712	ambiguous
REVEL	0.658	pathogenic-leaning
SaProt	LLR -8.67	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.78	acceptor loss · deltas
Pangolin	Δ0.51	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 59 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,854 alleles

Overall 6.21e-05% 1/1,610,294 alleles · very rare exomes 1/1,458,340 · genomes 0/151,954 · 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.Val502Phe
Coding: c.1504G>T
MANE Select: NM_015474
Type: single nucleotide variant
Location: chr20:36898544 (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 502: a β-strand

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-val502phe (accessed [today's date]).

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