Is CSF3R p.Arg583His (c.1748G>A) pathogenic?

CSF3R p.Arg583His (c.1748G>A) is classified Conflicting classifications of pathogenicity in CSF3R (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-06). AlphaMissense: likely benign (0.0554); Rare (popmax 0.461%, afr); Associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

What condition is associated with CSF3R p.Arg583His (c.1748G>A)?

CSF3R p.Arg583His (c.1748G>A) is associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency (ClinVar).

How common is CSF3R p.Arg583His (c.1748G>A) in the general population?

CSF3R p.Arg583His (c.1748G>A) is rare (popmax 0.461%, afr) (gnomAD).

What do computational predictors say about CSF3R p.Arg583His (c.1748G>A)?

AlphaMissense predicts likely benign (score 0.0554) — an in-silico prediction, not a clinical call.

CSF3R p.Arg583His

Q: How is Autosomal recessive severe congenital neutropenia due to CSF3R deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1748G>A · rs148104401 · VCV432323

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0554 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.461%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Computational evidence

Protein change
AlphaMissense	0.0554	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -7.27	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 -3.5	GERP -3.2
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 3.4e-07 · regional, not allelic
Overall
CADD	0.18	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 0.461% African / African-American · 346/75,058 alleles

Filtering AF 0.421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.405%

Overall 0.0282% 455/1,614,192 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.461%	217
Remaining individualsnot grpmax-eligible	0.0704%	1,421
Admixed American	0.0666%	1,501
Middle Eastern	0.033%	3,031
East Asian	0.00668%	14,961
South Asian	0.00329%	30,363
European (non-Finnish)	0.00144%	69,415

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: CSF3R
Protein: p.Arg583His
Coding: c.1748G>A
MANE Select: NM_000760
dbSNP: rs148104401
Type: single nucleotide variant
Location: chr1:36467938 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 1 PDB
Residue 583: the fibronectin type-iii 5 domain; a UniProt-annotated variant site (in)

Full CSF3R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive severe congenital neutropenia due to CSF3R deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CSF3R p.Arg583Cys Uncertain significance ★ ⚠ same residue
CSF3R c.1072-1G>A Pathogenic/Likely pathogenic ★★ same condition
CSF3R c.843+2T>C Pathogenic/Likely pathogenic ★★ same condition
CSF3R c.998-2A>T Likely pathogenic ★★ same condition
CSF3R p.Arg308Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CSF3R p.Arg440Ter Pathogenic ★★ same condition
CSF3R p.Gln114Ter Pathogenic/Likely pathogenic ★★ same condition
CSF3R p.Thr618Ile 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/csf3r-p-arg583his (accessed [today's date]).

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