Is CSF2RB p.Arg461Cys (c.1381C>T) pathogenic?

CSF2RB p.Arg461Cys (c.1381C>T) is classified Uncertain significance in CSF2RB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.1866); Ultra-rare (popmax 0.0966%, sas); Associated with surfactant metabolism dysfunction, pulmonary, 5.

What condition is associated with CSF2RB p.Arg461Cys (c.1381C>T)?

CSF2RB p.Arg461Cys (c.1381C>T) is associated with surfactant metabolism dysfunction, pulmonary, 5 (ClinVar).

How common is CSF2RB p.Arg461Cys (c.1381C>T) in the general population?

CSF2RB p.Arg461Cys (c.1381C>T) is ultra-rare (popmax 0.0966%, sas) (gnomAD).

How is Hereditary pulmonary alveolar proteinosis inherited?

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

What do computational predictors say about CSF2RB p.Arg461Cys (c.1381C>T)?

AlphaMissense predicts likely benign (score 0.1866) — an in-silico prediction, not a clinical call.

CSF2RB p.Arg461Cys

c.1381C>T · rs371045078 · VCV1390682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

surfactant metabolism dysfunction, pulmonary, 5

Computational evidence

Protein change
AlphaMissense	0.1866	likely benign
REVEL	0.643	indeterminate
SaProt	LLR -1.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 14 kb · p 0.00014 · regional, not allelic
Overall
CADD	25.3	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 0.0966% South Asian · 88/91,082 alleles

Filtering AF 0.0803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.0126% 203/1,614,188 alleles · ultra-rare exomes 190/1,461,876 · genomes 13/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0966%	1,035
Remaining individualsnot grpmax-eligible	0.0256%	3,907
African / African-American	0.0147%	6,822
European (non-Finnish)	0.00712%	14,048
Admixed American	0.00333%	30,014
East Asian	0.00223%	44,886
Finnishnot grpmax-eligible	0.00156%	64,022

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: CSF2RB
Protein: p.Arg461Cys
Coding: c.1381C>T
MANE Select: NM_000395
dbSNP: rs371045078
Type: single nucleotide variant
Location: chr22:36935416 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.50 · 10 PDB
Residue 461: an α-helix

Full CSF2RB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

surfactant metabolism dysfunction, pulmonary, 5 — 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

CSF2RB p.Arg461His Uncertain significance ★★ ⚠ same residue
CSF2RB p.Arg461= Likely benign ★★ same residue
CSF2RB p.Arg211Gln Uncertain significance ★★ ⚠ same condition
CSF2RB p.Glu533Lys Uncertain significance ★★ ⚠ same condition
CSF2RB p.Gly845Ser Uncertain significance ★★ ⚠ same condition
CSF2RB p.Thr196Asn Uncertain significance ★★ ⚠ same condition
CSF2RB p.Thr50Ile Uncertain significance ★★ ⚠ same condition
CSF2RB p.Arg215His Benign/Likely benign ★★ 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/csf2rb-p-arg461cys (accessed [today's date]).

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