Is CSF1R p.Pro28= (c.84T>C) pathogenic?

CSF1R p.Pro28= (c.84T>C) is classified Benign in CSF1R (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 56.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with leukoencephalopathy, hereditary diffuse, with spheroids.

What condition is associated with CSF1R p.Pro28= (c.84T>C)?

CSF1R p.Pro28= (c.84T>C) is associated with leukoencephalopathy, hereditary diffuse, with spheroids, brain abnormalities, neurodegeneration, and dysosteosclerosis (ClinVar).

CSF1R p.Pro28=

Q: How common is CSF1R p.Pro28= (c.84T>C) in the general population?

CSF1R p.Pro28= (c.84T>C) is common (popmax 56.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.84T>C · rs216123 · VCV352179

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 56.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.53	GERP -4.4, phastCons 0.001
Overall
CADD	2.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.2% European (non-Finnish) · 662,632/1,179,540 alleles

Filtering AF 56.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 56%

Overall 52.5% 847,564/1,613,380 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	70%	1
European (non-Finnish)grpmax	56.2%	2
Remaining individualsnot grpmax-eligible	49.5%	2
Middle Eastern	48%	2
Ashkenazi Jewishnot grpmax-eligible	47.8%	2
South Asian	46.8%	2
Amishnot grpmax-eligible	46.7%	2
Admixed American	37.1%	3
African / African-American	29.4%	3
East Asian	11%	9

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro28=
Coding: c.84T>C
MANE Select: NM_001288705
dbSNP: rs216123
Type: single nucleotide variant
Location: chr5:150080990 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 28: the ig-like c2-type 1 domain; a β-strand

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

Disease context

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

Also linked: brain abnormalities, neurodegeneration, and dysosteosclerosis

Similar variants

CSF1R p.Ala781Val 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.Gln481Ter Pathogenic ★★ same condition
CSF1R p.Gln877Ter Likely pathogenic ★★ same condition
CSF1R p.Glu633Lys 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-pro28 (accessed [today's date]).

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