Is SFTPB p.Ile75= (c.225C>T) pathogenic?

SFTPB p.Ile75= (c.225C>T) is classified Conflicting classifications of pathogenicity in SFTPB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-23). Ultra-rare (popmax 0.0137%, nfe); Associated with surfactant metabolism dysfunction, pulmonary, 1.

What condition is associated with SFTPB p.Ile75= (c.225C>T)?

SFTPB p.Ile75= (c.225C>T) is associated with surfactant metabolism dysfunction, pulmonary, 1, hereditary pulmonary alveolar proteinosis (ClinVar).

How common is SFTPB p.Ile75= (c.225C>T) in the general population?

SFTPB p.Ile75= (c.225C>T) is ultra-rare (popmax 0.0137%, nfe) (gnomAD).

How is Neonatal acute respiratory distress syndrome inherited?

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

SFTPB p.Ile75=

c.225C>T · rs145895555 · VCV896680

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, nfe)

Conditions

surfactant metabolism dysfunction, pulmonary, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.051	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -3.1, phastCons 0.006
Overall
CADD	11.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0137% European (non-Finnish) · 162/1,179,824 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0119% 192/1,613,762 alleles · ultra-rare exomes 175/1,461,650 · genomes 17/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0137%	7,283
Admixed American	0.0133%	7,498
Remaining individualsnot grpmax-eligible	0.0128%	7,808
South Asian	0.00769%	13,010
African / African-American	0.00668%	14,980
East Asian	0.00446%	22,439

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: SFTPB
Protein: p.Ile75=
Coding: c.225C>T
MANE Select: NM_000542
dbSNP: rs145895555
Type: single nucleotide variant
Location: chr2:85667148 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.31 · 9 PDB
Residue 75: the saposin b-type 1 domain

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

Disease context

surfactant metabolism dysfunction, pulmonary, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary pulmonary alveolar proteinosis

For Neonatal acute respiratory distress syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

SFTPB c.195+1G>A Pathogenic/Likely pathogenic ★★ same condition
SFTPB c.582+5G>A Uncertain significance ★★ same condition
SFTPB c.*922G>A Uncertain significance ★★ same condition
SFTPB p.Ala184Pro Uncertain significance ★★ ⚠ same condition
SFTPB p.Arg165Gln Uncertain significance ★★ ⚠ same condition
SFTPB p.Arg217Gln Uncertain significance ★★ ⚠ same condition
SFTPB p.Arg276Gln Uncertain significance ★★ ⚠ same condition
SFTPB p.Arg276Trp 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/sftpb-p-ile75 (accessed [today's date]).

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