Is SAMHD1 p.Pro26Leu (c.77C>T) pathogenic?

SAMHD1 p.Pro26Leu (c.77C>T) is classified Conflicting classifications of pathogenicity in SAMHD1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-12). AlphaMissense: likely benign (0.081); Rare (popmax 0.851%, afr); Associated with Aicardi-Goutieres syndrome 5.

What condition is associated with SAMHD1 p.Pro26Leu (c.77C>T)?

SAMHD1 p.Pro26Leu (c.77C>T) is associated with Aicardi-Goutieres syndrome 5, chilblain lupus 2, Aicardi-Goutieres syndrome (ClinVar).

How common is SAMHD1 p.Pro26Leu (c.77C>T) in the general population?

SAMHD1 p.Pro26Leu (c.77C>T) is rare (popmax 0.851%, afr) (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.Pro26Leu (c.77C>T)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

SAMHD1 p.Pro26Leu

c.77C>T · rs147240777 · VCV338350

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.851%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 5

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -7.55	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 -0.19	GERP -3.2
Regional constraint	o/e 0.85	unconstrained · MANE · 59 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	7.892	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 0.851% African / African-American · 639/75,066 alleles

Filtering AF 0.797% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.775%

Overall 0.045% 726/1,614,204 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.851%	117
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Admixed American	0.0566%	1,766
Middle Eastern	0.033%	3,030
South Asian	0.00329%	30,362
European (non-Finnish)	0.000169%	590,005

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.Pro26Leu
Coding: c.77C>T
MANE Select: NM_015474
dbSNP: rs147240777
Type: single nucleotide variant
Location: chr20:36951567 (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 26: the 'disordered' region

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: chilblain lupus 2 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.Pro26Ser Uncertain significance ★ ⚠ same residue
SAMHD1 p.Pro26= Likely benign ★ 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

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-pro26leu (accessed [today's date]).

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