# NM_001317778.2(SFTPC):c.24C>G (p.Val8=)

https://sugi.bio/variant/sftpc-p-val8

## Summary

**SFTPC p.Val8= (c.24C>G)** is classified **Benign/Likely benign** in SFTPC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0403%, nfe); Associated with surfactant metabolism dysfunction, pulmonary, 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs144603526 · 6 submitters · 2 linked conditions · ultra-rare (popmax 0.0403%, nfe)

## For patients & families {#patients}

This is a change in the SFTPC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 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.Val8= |
| Coding change (HGVS c.) | c.24C>G |
| MANE Select transcript | [NM_001317778](https://www.ncbi.nlm.nih.gov/nuccore/NM_001317778) |
| dbSNP | [rs144603526](https://www.ncbi.nlm.nih.gov/snp/rs144603526/) |
| Variant type | single nucleotide variant |
| Location | chr8:22161852-22161852 (GRCh38) |
| ClinVar | [VCV362550](https://www.ncbi.nlm.nih.gov/clinvar/variation/362550/) |

**All HGVS expressions:** `NC_000008.10:g.22019365C>G`, `NC_000008.11:g.22161852C>G`, `NG_016968.1:g.5182C>G`, `NG_029659.1:g.1713C>G`, `NM_001172357.2:c.24C>G`, `NM_001172410.2:c.24C>G`, `NM_001317778.2:c.24C>G`, `NM_001317779.2:c.24C>G`, `NM_001317780.2:c.24C>G`, `NM_003018.4:c.24C>G`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.752, GERP -0.838, phastCons 0.97 — weakly conserved position
- CADD: **PHRED 9.85**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.46 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0403%** (nfe) · FAF95 0.0373% · FAF99 0.0361% · 476/1,180,004 in the highest group · 1,430/1,614,032 alleles overall — ultra-rare (popmax 0.0403%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.72% | 37 |
| Remaining individuals (not grpmax-eligible) | 0.19% | 525 |
| European (non-Finnish) (grpmax) | 0.0403% | 2,479 |
| Admixed American | 0.0333% | 3,001 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.00933% | 10,719 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,940 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


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. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-14.

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

**Submission history:** 6 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Johns Hopkins Genomics, Johns Hopkins University | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-29 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-10-14 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-10-06 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[surfactant metabolism dysfunction, pulmonary, 2](https://sugi.bio/atlas/disease/surfactant-metabolism-dysfunction-pulmonary-2/), [hereditary pulmonary alveolar proteinosis](https://sugi.bio/atlas/disease/hereditary-pulmonary-alveolar-proteinosis/).

**Reported phenotype names (ClinVar):** Surfactant metabolism dysfunction, pulmonary, 2, not provided, Hereditary pulmonary alveolar proteinosis, Lung cancer, DESQUAMATIVE INTERSTITIAL PNEUMONITIS DUE TO SURFACTANT PROTEIN C DEFICIENCY, INTERSTITIAL LUNG DISEASE DUE TO SURFACTANT PROTEIN C DEFICIENCY, PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 2, Pulmonary surfactant metabolism dysfunction, none provided.

## Similar variants {#similar}

Related SFTPC variant pages (same residue, condition, or type): [SFTPC p.Val8Leu](/variant/sftpc-p-val8leu), [SFTPC p.Val8Phe](/variant/sftpc-p-val8phe), [SFTPC c.435+2T>C](/variant/sftpc-c-435-plus-2t-c), [SFTPC p.Ile73Thr](/variant/sftpc-p-ile73thr), [SFTPC p.Leu110Pro](/variant/sftpc-p-leu110pro), [SFTPC c.*193C>A](/variant/sftpc-c-star-193c-a), [SFTPC p.Ile50Met](/variant/sftpc-p-ile50met), [SFTPC p.Leu45Pro](/variant/sftpc-p-leu45pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 362550). 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.*