# NM_001317778.2(SFTPC):c.228G>A (p.Pro76=)

https://sugi.bio/variant/sftpc-p-pro76

## Summary

**SFTPC p.Pro76= (c.228G>A)** is classified **Benign/Likely benign** in SFTPC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-05). Rare (popmax 0.733%, eas); Associated with interstitial lung disease 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs75413490 · 4 submitters · 3 linked conditions · rare (popmax 0.733%, eas)

## 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 4 submitters, and is linked to interstitial lung disease 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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028066/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.Pro76= |
| Coding change (HGVS c.) | c.228G>A |
| MANE Select transcript | [NM_001317778](https://www.ncbi.nlm.nih.gov/nuccore/NM_001317778) |
| dbSNP | [rs75413490](https://www.ncbi.nlm.nih.gov/snp/rs75413490/) |
| Variant type | single nucleotide variant |
| Location | chr8:22163106-22163106 (GRCh38) |
| ClinVar | [VCV362555](https://www.ncbi.nlm.nih.gov/clinvar/variation/362555/) |

**All HGVS expressions:** `NC_000008.10:g.22020619G>A`, `NC_000008.11:g.22163106G>A`, `NG_016968.1:g.6436G>A`, `NG_029659.1:g.2967G>A`, `NM_001172357.2:c.228G>A`, `NM_001172410.2:c.228G>A`, `NM_001317778.2:c.228G>A`, `NM_001317779.2:c.69G>A`, `NM_001317780.2:c.228G>A`, `NM_003018.4:c.228G>A`

## 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 -9.916, GERP -3.13 — fast-evolving / accelerated position
- CADD: **PHRED 0.085**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.733%** (eas) · FAF95 0.668% · FAF99 0.642% · 329/44,876 in the highest group · 408/1,614,144 alleles overall — rare (popmax 0.733%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.21% | 83 |
| East Asian (grpmax) | 0.733% | 136 |
| South Asian | 0.0494% | 2,024 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,945 |
| Admixed American | 0.00167% | 60,024 |
| African / African-American | 0.00133% | 75,034 |
| European (non-Finnish) | 0.00102% | 98,335 |

Amish 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 2024-11-05.

**Submitter consensus:** conflicting (3 Benign, 2 Likely benign).

**Submission history:** 5 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-05-04 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-11-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Interstitial lung disease 2, Surfactant metabolism dysfunction, pulmonary, 2, Hereditary pulmonary alveolar proteinosis, not provided, not specified, none provided, Familial idiopathic pulmonary fibrosis, FIBROCYSTIC PULMONARY DYSPLASIA, FIBROSING ALVEOLITIS, CRYPTOGENIC, AllHighlyPenetrant.

## Similar variants {#similar}

Related SFTPC variant pages (same residue, condition, or type): [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), [SFTPC p.Val39Met](/variant/sftpc-p-val39met), [SFTPC c.201+14G>A](/variant/sftpc-c-201-plus-14g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 362555). 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.*