Is CSF1R p.Ala245Ser (c.733G>T) pathogenic?

CSF1R p.Ala245Ser (c.733G>T) is classified Benign in CSF1R (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0689); Common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele; Associated with leukoencephalopathy, hereditary diffuse, with spheroids.

What condition is associated with CSF1R p.Ala245Ser (c.733G>T)?

CSF1R p.Ala245Ser (c.733G>T) is associated with leukoencephalopathy, hereditary diffuse, with spheroids (ClinVar).

What do computational predictors say about CSF1R p.Ala245Ser (c.733G>T)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

CSF1R p.Ala245Ser

Q: How common is CSF1R p.Ala245Ser (c.733G>T) in the general population?

CSF1R p.Ala245Ser (c.733G>T) is common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.733G>T · rs41338945 · VCV352163

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -2.85	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 -3.2	GERP -3.8
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	0.002	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 9.56% African / African-American · 7,162/74,910 alleles

Filtering AF 9.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3%

Overall 0.502% 8,090/1,610,236 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.56%	10
Remaining individualsnot grpmax-eligible	0.609%	164
Admixed American	0.585%	171
Middle Eastern	0.43%	233
South Asian	0.0165%	6,059
European (non-Finnish)	0.0133%	7,544

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.Ala245Ser
Coding: c.733G>T
MANE Select: NM_001288705
dbSNP: rs41338945
Type: single nucleotide variant
Location: chr5:150077432 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 245: a disulfide bond; a UniProt-annotated variant site (in); the ig-like c2-type 3 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.Ala245= Likely benign ★ same residue
CSF1R p.Ala245Thr Benign ★ same residue
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

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-ala245ser (accessed [today's date]).

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