Is SFTPB p.Pro159Arg (c.476C>G) pathogenic?

SFTPB p.Pro159Arg (c.476C>G) is classified Uncertain significance in SFTPB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-03). AlphaMissense: likely benign (0.0761); Absent from gnomAD v4.1; Associated with hereditary pulmonary alveolar proteinosis.

What condition is associated with SFTPB p.Pro159Arg (c.476C>G)?

SFTPB p.Pro159Arg (c.476C>G) is associated with hereditary pulmonary alveolar proteinosis (ClinVar).

How common is SFTPB p.Pro159Arg (c.476C>G) in the general population?

SFTPB p.Pro159Arg (c.476C>G) is absent from gnomAD v4.1 (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 SFTPB p.Pro159Arg (c.476C>G)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

SFTPB p.Pro159Arg

c.476C>G · rs2466687289 · VCV1745529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pulmonary alveolar proteinosis

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.90	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 0.43	GERP -1.4, phastCons 0.83
Regional constraint	o/e 0.88	unconstrained · MANE · 6,707 bp · p 0.0066 · regional, not allelic
Overall
CADD	11.89	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SFTPB
Protein: p.Pro159Arg
Coding: c.476C>G
MANE Select: NM_000542
dbSNP: rs2466687289
Type: single nucleotide variant
Location: chr2:85665712 (GRCh38)
Gene constraint: LOEUF 0.846 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.31 · 9 PDB

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

Disease context

hereditary pulmonary alveolar proteinosis — 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

SFTPB p.Pro159Leu Uncertain significance ★ ⚠ same residue
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
SFTPB p.Asp118Asn Uncertain significance ★★ ⚠ same condition
SFTPB p.Asp158His 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-pro159arg (accessed [today's date]).

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