Is CSF1R p.Asp439Ala (c.1316A>C) pathogenic?

CSF1R p.Asp439Ala (c.1316A>C) is classified Uncertain significance in CSF1R (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.00834%, amr); Associated with leukoencephalopathy, diffuse hereditary, with spheroids 1.

What condition is associated with CSF1R p.Asp439Ala (c.1316A>C)?

CSF1R p.Asp439Ala (c.1316A>C) is associated with leukoencephalopathy, diffuse hereditary, with spheroids 1, CSF1R-related disorder (ClinVar).

How common is CSF1R p.Asp439Ala (c.1316A>C) in the general population?

CSF1R p.Asp439Ala (c.1316A>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CSF1R p.Asp439Ala (c.1316A>C)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

CSF1R p.Asp439Ala

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.1316A>C · rs771614491 · VCV2188912

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, diffuse hereditary, with spheroids 1

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 2.5, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	24.7	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 0.00834% Admixed American · 5/59,974 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000682% 11/1,613,610 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,995
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)	0.000254%	393,284

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.Asp439Ala
Coding: c.1316A>C
MANE Select: NM_001288705
dbSNP: rs771614491
Type: single nucleotide variant
Location: chr5:150070185 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 439: a disulfide bond; the ig-like c2-type 5 domain

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

Also linked: CSF1R-related disorder

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

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CSF1R p.Asp439= Likely benign ★★ same residue
CSF1R p.Ala780Val Likely pathogenic ★★ same condition
CSF1R p.Arg676Ter Pathogenic ★★ same condition
CSF1R p.Arg777Gln Pathogenic ★★ same condition
CSF1R p.Arg777Trp Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Arg782Cys Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Arg782His Pathogenic/Likely pathogenic ★★ same condition
CSF1R p.Gln642Ter 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-asp439ala (accessed [today's date]).

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