Is CSF1R p.Cys653Arg (c.1957T>C) pathogenic?

CSF1R p.Cys653Arg (c.1957T>C) is classified Uncertain significance in CSF1R (ClinVar, Single submitter, 2 submitters; last evaluated 2019-10-22). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with leukoencephalopathy, hereditary diffuse, with spheroids.

What condition is associated with CSF1R p.Cys653Arg (c.1957T>C)?

CSF1R p.Cys653Arg (c.1957T>C) is associated with leukoencephalopathy, hereditary diffuse, with spheroids (ClinVar).

How common is CSF1R p.Cys653Arg (c.1957T>C) in the general population?

CSF1R p.Cys653Arg (c.1957T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CSF1R p.Cys653Arg (c.1957T>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

CSF1R p.Cys653Arg

c.1957T>C · rs690016559 · VCV162123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,608,286)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 3% in CSF1R
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,956 bp · p 6.2e-07 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,608,286). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CSF1R
Protein: p.Cys653Arg
Coding: c.1957T>C
MANE Select: NM_001288705
dbSNP: rs690016559
Type: single nucleotide variant
Location: chr5:150060874 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 653: the protein kinase domain; a β-strand; a UniProt-annotated variant site (in banddos); a UniProt-annotated variant site (in hdls1)

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.Cys653Tyr Likely pathogenic ★ same residue
CSF1R p.Cys653= Likely 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-cys653arg (accessed [today's date]).

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