Is CSF2RA p.Arg227His (c.680G>A) pathogenic?

CSF2RA p.Arg227His (c.680G>A) is classified Uncertain significance in CSF2RA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). Very rare (popmax 0.00891%, eas); Associated with surfactant metabolism dysfunction, pulmonary, 4.

What condition is associated with CSF2RA p.Arg227His (c.680G>A)?

CSF2RA p.Arg227His (c.680G>A) is associated with surfactant metabolism dysfunction, pulmonary, 4 (ClinVar).

How common is CSF2RA p.Arg227His (c.680G>A) in the general population?

CSF2RA p.Arg227His (c.680G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

How is Hereditary pulmonary alveolar proteinosis inherited?

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

CSF2RA p.Arg227His

c.680G>A · rs761247845 · VCV1424688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

surfactant metabolism dysfunction, pulmonary, 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.169	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -8.9
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.2 · regional, not allelic
Overall
CADD	0.003	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,882 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00124% 20/1,613,716 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
South Asian	0.00439%	22,768
Remaining individualsnot grpmax-eligible	0.0016%	62,458
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000848%	117,984

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: CSF2RA
Protein: p.Arg227His
Coding: c.680G>A
MANE Select: NM_172245
dbSNP: rs761247845
Type: single nucleotide variant
Location: chrX:1294361 (GRCh38)
Structure: AlphaFold pLDDT 82.15 · 2 PDB
Residue 227: a β-strand; the fibronectin type-iii domain

Full CSF2RA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

surfactant metabolism dysfunction, pulmonary, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary pulmonary alveolar proteinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CSF2RA p.Arg227= Conflicting classifications of pathogenicity ★ same residue
CSF2RA p.Arg227Cys Uncertain significance ★ same residue
CSF2RA p.Arg199Ter Pathogenic ★★ same condition
CSF2RA p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
CSF2RA p.Gln204Ter Pathogenic ★★ same condition
CSF2RA p.Gln263Ter Pathogenic/Likely pathogenic ★★ same condition
CSF2RA p.Arg354Gln Uncertain significance ★★ same condition
CSF2RA p.Gly339Val Uncertain significance ★★ 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/csf2ra-p-arg227his (accessed [today's date]).

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