Is CSF1R p.Pro90Thr (c.268C>A) pathogenic?

CSF1R p.Pro90Thr (c.268C>A) is classified Benign/Likely benign in CSF1R (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0732); Rare (popmax 0.656%, afr); Associated with leukoencephalopathy, hereditary diffuse, with spheroids.

What condition is associated with CSF1R p.Pro90Thr (c.268C>A)?

CSF1R p.Pro90Thr (c.268C>A) is associated with leukoencephalopathy, hereditary diffuse, with spheroids (ClinVar).

How common is CSF1R p.Pro90Thr (c.268C>A) in the general population?

CSF1R p.Pro90Thr (c.268C>A) is rare (popmax 0.656%, afr) (gnomAD).

What do computational predictors say about CSF1R p.Pro90Thr (c.268C>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

CSF1R p.Pro90Thr

c.268C>A · rs150475750 · VCV352173

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.656%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -7.18	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 0.16	GERP -0.21, phastCons 0.45
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	5.21	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 0.656% African / African-American · 492/75,020 alleles

Filtering AF 0.608% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.589%

Overall 0.0406% 655/1,614,144 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.656%	152
Middle Eastern	0.181%	551
Remaining individualsnot grpmax-eligible	0.0608%	1,645
Admixed American	0.0566%	1,765
European (non-Finnish)	0.00653%	15,325
South Asian	0.00329%	30,362

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.Pro90Thr
Coding: c.268C>A
MANE Select: NM_001288705
dbSNP: rs150475750
Type: single nucleotide variant
Location: chr5:150080806 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 90: the ig-like c2-type 1 domain

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

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-pro90thr (accessed [today's date]).

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