Is CSF1R p.Arg921Trp (c.2761C>T) pathogenic?

CSF1R p.Arg921Trp (c.2761C>T) is classified Benign in CSF1R (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0897); Ultra-rare (popmax 0.0317%, amr); Associated with leukoencephalopathy, hereditary diffuse, with spheroids.

What condition is associated with CSF1R p.Arg921Trp (c.2761C>T)?

CSF1R p.Arg921Trp (c.2761C>T) is associated with leukoencephalopathy, hereditary diffuse, with spheroids, CSF1R-related disorder (ClinVar).

How common is CSF1R p.Arg921Trp (c.2761C>T) in the general population?

CSF1R p.Arg921Trp (c.2761C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about CSF1R p.Arg921Trp (c.2761C>T)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

CSF1R p.Arg921Trp

c.2761C>T · rs202216061 · VCV352128

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.00	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 5.6	GERP -0.51, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 279 bp · p 0.48 · regional, not allelic
Overall
CADD	23.9	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 0.0317% Admixed American · 19/59,994 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.0113% 182/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.304%	329
Admixed Americangrpmax	0.0317%	3,158
Remaining individualsnot grpmax-eligible	0.0176%	5,680
South Asian	0.0176%	5,692
Middle Eastern	0.0164%	6,082
European (non-Finnish)	0.00356%	28,096
African / African-American	0.00267%	37,455
East Asian	0.00223%	44,886

Ashkenazi Jewish 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.Arg921Trp
Coding: c.2761C>T
MANE Select: NM_001288705
dbSNP: rs202216061
Type: single nucleotide variant
Location: chr5:150054324 (GRCh38)
Gene constraint: LOEUF 0.485 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 26 PDB
Residue 921: the 'disordered' region; a UniProt-annotated variant site (in banddos); a UniProt-annotated variant site (in)

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: CSF1R-related disorder

Similar variants

CSF1R p.Arg921Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CSF1R p.Arg921Gln 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-arg921trp (accessed [today's date]).

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