Is CSF1R p.Arg676Ter (c.2026C>T) pathogenic?

CSF1R p.Arg676Ter (c.2026C>T) is classified Pathogenic in CSF1R (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). Very rare (popmax 8.47e-05%, nfe); Associated with leukoencephalopathy, diffuse hereditary, with spheroids 1.

What condition is associated with CSF1R p.Arg676Ter (c.2026C>T)?

CSF1R p.Arg676Ter (c.2026C>T) is associated with leukoencephalopathy, diffuse hereditary, with spheroids 1 (ClinVar).

How common is CSF1R p.Arg676Ter (c.2026C>T) in the general population?

CSF1R p.Arg676Ter (c.2026C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CSF1R p.Arg676Ter

Q: How is Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia inherited?

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

c.2026C>T · rs1757422149 · VCV1322164

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

leukoencephalopathy, diffuse hereditary, with spheroids 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 14 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,844 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: CSF1R
Protein: p.Arg676Ter
Coding: c.2026C>T
MANE Select: NM_001288705
dbSNP: rs1757422149
Type: single nucleotide variant
Location: chr5:150059806 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 676: the protein kinase domain; an α-helix; a UniProt-annotated variant site (in banddos)

Full CSF1R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy, diffuse hereditary, with spheroids 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CSF1R p.Ala780Val Likely pathogenic ★★ same condition
CSF1R p.Arg777Gln Pathogenic ★★ same condition
CSF1R p.Arg782Cys Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Arg782His Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Glu633Lys Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Gly589Arg Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Gly591Glu Likely pathogenic ★★ same condition
CSF1R p.Ile794Thr 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/csf1r-p-arg676ter (accessed [today's date]).

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