Is SFTPC p.Leu45Pro (c.134T>C) pathogenic?

SFTPC p.Leu45Pro (c.134T>C) is classified Uncertain significance in SFTPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.8986); Very rare (popmax 0.000424%, nfe); Associated with surfactant metabolism dysfunction, pulmonary, 2.

What condition is associated with SFTPC p.Leu45Pro (c.134T>C)?

SFTPC p.Leu45Pro (c.134T>C) is associated with surfactant metabolism dysfunction, pulmonary, 2 (ClinVar).

How common is SFTPC p.Leu45Pro (c.134T>C) in the general population?

SFTPC p.Leu45Pro (c.134T>C) is very rare (popmax 0.000424%, nfe) (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 SFTPC p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely pathogenic (score 0.8986) — an in-silico prediction, not a clinical call.

SFTPC p.Leu45Pro

c.134T>C · rs948413532 · VCV2575233

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

surfactant metabolism dysfunction, pulmonary, 2

Computational evidence

Protein change
AlphaMissense	0.8986	likely pathogenic · top 4% in SFTPC
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -11.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,209 bp · p 0.036 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,180,026 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,198 alleles · very rare exomes 5/1,461,882 · genomes 0/152,316 · joint denominator

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: SFTPC
Protein: p.Leu45Pro
Coding: c.134T>C
MANE Select: NM_001317778
dbSNP: rs948413532
Type: single nucleotide variant
Location: chr8:22162665 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.71 · 3 PDB

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

Disease context

surfactant metabolism dysfunction, pulmonary, 2 — 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

SFTPC c.435+2T>C Pathogenic/Likely pathogenic ★★ same condition
SFTPC p.Ile73Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
SFTPC c.*193C>A Uncertain significance ★★ same condition
SFTPC p.Ile50Met Uncertain significance ★★ ⚠ same condition
SFTPC p.Val39Met Uncertain significance ★★ ⚠ same condition
SFTPC c.201+14G>A Benign/Likely benign ★★ same condition
SFTPC c.201+49C>A Benign ★★ same condition
SFTPC c.43-21T>C 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/sftpc-p-leu45pro (accessed [today's date]).

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