Is SAMHD1 p.Ser561Arg (c.1683T>G) pathogenic?

SAMHD1 p.Ser561Arg (c.1683T>G) is classified Uncertain significance in SAMHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely pathogenic (0.6522); Very rare (popmax 0.000254%, nfe).

How common is SAMHD1 p.Ser561Arg (c.1683T>G) in the general population?

SAMHD1 p.Ser561Arg (c.1683T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SAMHD1 p.Ser561Arg (c.1683T>G)?

AlphaMissense predicts likely pathogenic (score 0.6522) — an in-silico prediction, not a clinical call.

SAMHD1 p.Ser561Arg

c.1683T>G · VCV4944953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6522	likely pathogenic
REVEL	0.365	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.22, phastCons 0.96
Regional constraint	o/e 0.85	unconstrained · MANE · 59 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	16.58	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 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,882 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.Ser561Arg
Coding: c.1683T>G
MANE Select: NM_015474
Type: single nucleotide variant
Location: chr20:36897885 (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 561: 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

Similar variants

SAMHD1 p.Ser561fs Conflicting classifications of pathogenicity ★ same residue
SAMHD1 c.1062+1G>T Pathogenic/Likely pathogenic ★★ same type
SAMHD1 c.1411-2A>G Pathogenic ★★ same type
SAMHD1 c.509+1G>A Likely pathogenic ★★ same type
SAMHD1 c.626-1G>C Pathogenic/Likely pathogenic ★★ same type
SAMHD1 p.Arg106Ter Pathogenic/Likely pathogenic ★★ same type
SAMHD1 p.Arg134Ter Pathogenic/Likely pathogenic ★★ same type
SAMHD1 p.Arg143Cys Pathogenic/Likely pathogenic ★★ same type

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-ser561arg (accessed [today's date]).

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