Is CSF3R p.Arg274Cys (c.820C>T) pathogenic?

CSF3R p.Arg274Cys (c.820C>T) is classified Uncertain significance in CSF3R (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.1515); Very rare (popmax 0.00833%, amr); Associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

What condition is associated with CSF3R p.Arg274Cys (c.820C>T)?

CSF3R p.Arg274Cys (c.820C>T) is associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency (ClinVar).

How common is CSF3R p.Arg274Cys (c.820C>T) in the general population?

CSF3R p.Arg274Cys (c.820C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CSF3R p.Arg274Cys (c.820C>T)?

AlphaMissense predicts likely benign (score 0.1515) — an in-silico prediction, not a clinical call.

CSF3R p.Arg274Cys

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.820C>T · rs759587248 · VCV1337893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Computational evidence

Protein change
AlphaMissense	0.1515	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -9.02	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 3.4	GERP 0.43, phastCons 0.51
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 3.4e-07 · regional, not allelic
Overall
CADD	14.53	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00833% Admixed American · 5/60,022 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000752% 11/1,461,850 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,004
South Asian	0.00439%	22,772
European (non-Finnish)	0.000169%	590,016

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.Arg274Cys
Coding: c.820C>T
MANE Select: NM_000760
dbSNP: rs759587248
Type: single nucleotide variant
Location: chr1:36472540 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 1 PDB
Residue 274: a disulfide bond; a β-strand; the fibronectin type-iii 2 domain

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.Arg274His 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-arg274cys (accessed [today's date]).

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