Is CSF3R p.Arg418= (c.1254T>C) pathogenic?

CSF3R p.Arg418= (c.1254T>C) is classified Benign/Likely benign in CSF3R (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 40.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

What condition is associated with CSF3R p.Arg418= (c.1254T>C)?

CSF3R p.Arg418= (c.1254T>C) is associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency (ClinVar).

CSF3R p.Arg418=

Q: How common is CSF3R p.Arg418= (c.1254T>C) in the general population?

CSF3R p.Arg418= (c.1254T>C) is common (popmax 40.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1254T>C · rs3917980 · VCV256789

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 40.6%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.008	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.2
Overall
CADD	0.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.6% South Asian · 37,001/91,074 alleles

Filtering AF 40.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.1%

Overall 32.9% 531,212/1,613,654 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	57.8%	2
South Asiangrpmax	40.6%	2
Ashkenazi Jewishnot grpmax-eligible	36.5%	3
Middle Eastern	35.7%	3
Finnishnot grpmax-eligible	34.4%	3
European (non-Finnish)	34.3%	3
Remaining individualsnot grpmax-eligible	31.4%	3
Admixed American	25.8%	4
African / African-American	19.4%	5
East Asian	8.73%	11

Amish 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: CSF3R
Protein: p.Arg418=
Coding: c.1254T>C
MANE Select: NM_000760
dbSNP: rs3917980
Type: single nucleotide variant
Location: chr1:36471464 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 1 PDB
Residue 418: the fibronectin type-iii 3 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.Arg418His Conflicting classifications of pathogenicity ★ ⚠ 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-arg418 (accessed [today's date]).

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