# NM_001317778.2(SFTPC):c.445G>C (p.Ala149Pro)

https://sugi.bio/variant/sftpc-p-ala149pro

## Summary

**SFTPC p.Ala149Pro (c.445G>C)** is classified **Conflicting classifications of pathogenicity** in SFTPC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.0991); Ultra-rare (popmax 0.0274%, sas); Associated with surfactant metabolism dysfunction, pulmonary, 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs202145169 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0274%, sas)

## For patients & families {#patients}

This is a change in the SFTPC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to surfactant metabolism dysfunction, pulmonary, 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | SFTPC is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hereditary pulmonary alveolar proteinosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal circulating protein level — Very frequent (99-80%)
- Failure to thrive in infancy — Frequent (79-30%)
- Restrictive ventilatory defect — Frequent (79-30%)
- Respiratory distress — Frequent (79-30%)
- Respiratory failure requiring assisted ventilation — Frequent (79-30%)
- Hypoxemia — Frequent (79-30%)
- Crazy paving pattern on pulmonary HRCT — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025399/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SFTPC](https://sugi.bio/atlas/gene/SFTPC/) |
| Protein change (HGVS p.) | p.Ala149Pro |
| Coding change (HGVS c.) | c.445G>C |
| MANE Select transcript | [NM_001317778](https://www.ncbi.nlm.nih.gov/nuccore/NM_001317778) |
| dbSNP | [rs202145169](https://www.ncbi.nlm.nih.gov/snp/rs202145169/) |
| Variant type | single nucleotide variant |
| Location | chr8:22163910-22163910 (GRCh38) |
| ClinVar | [VCV362560](https://www.ncbi.nlm.nih.gov/clinvar/variation/362560/) |

**All HGVS expressions:** `NC_000008.10:g.22021423G>C`, `NC_000008.11:g.22163910G>C`, `NG_016968.1:g.7240G>C`, `NG_029659.1:g.3771G>C`, `NM_001172357.2:c.445G>C`, `NM_001172410.2:c.463G>C`, `NM_001317778.2:c.445G>C`, `NM_001317779.2:c.304G>C`, `NM_001317780.2:c.445G>C`, `NM_003018.4:c.463G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0991)
- REVEL 0.547 (indeterminate)
- SaProt LLR -6.033 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 1.415, GERP -0.896, phastCons 0.002 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A155P** vs ClinVar **A149P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 11.75**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.87** across the covering region of the MANE Select transcript (22,161,829–22,164,038), spanning 2,209 bp. Chi-square p 0.036. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for SFTPC (237 scored positions, the nearest 9 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0274%** (sas) · FAF95 0.019% · FAF99 0.0163% · 25/91,086 in the highest group · 256/1,613,812 alleles overall — ultra-rare (popmax 0.0274%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0274% | 3,643 |
| European (non-Finnish) | 0.0182% | 5,488 |
| Middle Eastern | 0.0166% | 6,034 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,250 |
| Admixed American | 0.00666% | 15,009 |
| African / African-American | 0.00133% | 75,068 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SFTPC** population constraint: LOEUF 1, pLI 0.0031214, missense-Z 1.0693. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **SFTPC-related interstitial lung disease** — Definitive (AD)

## Protein context {#protein}

Residue **155** lies in a β-strand; the brichos domain.

AlphaFold model confidence (whole protein): pLDDT 70.71, 33% of residues very-high.

**3 experimental structure(s)** (PDB): [2YAD](https://www.rcsb.org/structure/2YAD), [8OVI](https://www.rcsb.org/structure/8OVI), [8OX2](https://www.rcsb.org/structure/8OX2).

## What this gene does {#gene-function}

*Describes the biological roles of SFTPC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SFTPC's established molecular role includes identical protein binding. p.Ala149Pro falls in the brichos domain. In Reactome, SFTPC is annotated in disease pathway(s) including **Defective CSF2RA causes SMDP4**, **Defective CSF2RB causes SMDP5**.

**Disease mechanism (Reactome):** SFTPC loss or alteration is curated in [Defective CSF2RA causes SMDP4](https://reactome.org/content/detail/R-HSA-5688890), [Defective CSF2RB causes SMDP5](https://reactome.org/content/detail/R-HSA-5688849), [Defective pro-SFTPC causes SMDP2 and RDS](https://reactome.org/content/detail/R-HSA-5688354).

### Pathways affected {#pathways}

SFTPC participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CSF2RA causes SMDP4](https://reactome.org/content/detail/R-HSA-5688890) | curated |
| ⚕ [Defective CSF2RB causes SMDP5](https://reactome.org/content/detail/R-HSA-5688849) | curated |
| ⚕ [Defective pro-SFTPC causes SMDP2 and RDS](https://reactome.org/content/detail/R-HSA-5688354) | curated |
| [Surfactant metabolism](https://reactome.org/content/detail/R-HSA-5683826) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-21.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2017–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |

## Associated conditions {#conditions}

[surfactant metabolism dysfunction, pulmonary, 2](https://sugi.bio/atlas/disease/surfactant-metabolism-dysfunction-pulmonary-2/), [interstitial lung disease 2](https://sugi.bio/atlas/disease/interstitial-lung-disease-2/).

**Reported phenotype names (ClinVar):** Surfactant metabolism dysfunction, pulmonary, 2, Interstitial lung disease 2, not provided, not specified, AllHighlyPenetrant, INTERSTITIAL LUNG DISEASE DUE TO SURFACTANT PROTEIN C DEFICIENCY, DESQUAMATIVE INTERSTITIAL PNEUMONITIS DUE TO SURFACTANT PROTEIN C DEFICIENCY, PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 2, Familial idiopathic pulmonary fibrosis, FIBROCYSTIC PULMONARY DYSPLASIA.

## Same-residue context {#hotspot}

Residue **149** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SFTPC p.Ala149fs](/variant/sftpc-p-ala149fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SFTPC variant pages (same residue, condition, or type): [SFTPC p.Ala149Ser](/variant/sftpc-p-ala149ser), [SFTPC p.Ala149fs](/variant/sftpc-p-ala149fs), [SFTPC c.435+2T>C](/variant/sftpc-c-435-plus-2t-c), [SFTPC p.Ile73Thr](/variant/sftpc-p-ile73thr), [SFTPC c.*193C>A](/variant/sftpc-c-star-193c-a), [SFTPC p.Ile50Met](/variant/sftpc-p-ile50met), [SFTPC p.Leu45Pro](/variant/sftpc-p-leu45pro), [SFTPC p.Val39Met](/variant/sftpc-p-val39met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 362560). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*