# NM_000631.5(NCF4):c.409C>T (p.Pro137Ser)

https://sugi.bio/variant/ncf4-p-pro137ser

## Summary

**NCF4 p.Pro137Ser (c.409C>T)** is classified **Conflicting classifications of pathogenicity** in NCF4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-24). AlphaMissense: likely benign (0.0631); Very rare (popmax 0.000847%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1160758215 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000847%, nfe)

## For patients & families {#patients}

This is a change in the NCF4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

*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, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | NCF4 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Chronic granulomatous disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sinusitis — Very frequent (99-80%)
- Otitis media — Very frequent (99-80%)
- Cutaneous photosensitivity — Very frequent (99-80%)
- Hypermelanotic macule — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Pyloric stenosis — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015736/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NCF4](https://sugi.bio/atlas/gene/NCF4/) |
| Protein change (HGVS p.) | p.Pro137Ser |
| Coding change (HGVS c.) | c.409C>T |
| MANE Select transcript | [NM_000631](https://www.ncbi.nlm.nih.gov/nuccore/NM_000631) |
| dbSNP | [rs1160758215](https://www.ncbi.nlm.nih.gov/snp/rs1160758215/) |
| Variant type | single nucleotide variant |
| Location | chr22:36870481-36870481 (GRCh38) |
| ClinVar | [VCV1384830](https://www.ncbi.nlm.nih.gov/clinvar/variation/1384830/) |

**All HGVS expressions:** `LRG_159:g.14494C>T`, `LRG_159t1:c.409C>T`, `NC_000022.10:g.37266523C>T`, `NC_000022.11:g.36870481C>T`, `NG_023400.1:g.14494C>T`, `NM_000631.5:c.409C>T`, `NM_013416.3:c.409C>T`, `NM_013416.4:c.409C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0631)
- REVEL 0.009 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.576 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -5.859, GERP -2.84 — fast-evolving / accelerated position
- CADD: **PHRED 0.097**. 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 0.94** across the covering region of the MANE Select transcript (36,861,172–36,877,820), spanning 16,648 bp. Chi-square p 0.18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.000847%** (nfe) · FAF95 0.000429% · FAF99 0.000312% · 10/1,180,040 in the highest group · 11/1,613,790 alleles overall — very rare (popmax 0.000847%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| European (non-Finnish) (grpmax) | 0.000847% | 118,004 |

Remaining individuals 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}

**NCF4** population constraint: LOEUF 1.005, pLI 2.8817e-08, missense-Z 0.52693; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **137** lies in the px domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.48, 48% of residues very-high.

**6 experimental structure(s)** (PDB): [1H6H](https://www.rcsb.org/structure/1H6H), [1OEY](https://www.rcsb.org/structure/1OEY), [1W6X](https://www.rcsb.org/structure/1W6X), [1W70](https://www.rcsb.org/structure/1W70), [1Z9Q](https://www.rcsb.org/structure/1Z9Q), [2DYB](https://www.rcsb.org/structure/2DYB).

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

*Describes the biological roles of NCF4 (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:** NCF4's established molecular role includes superoxide-generating NADPH oxidase activator activity. p.Pro137Ser falls in the px domain.


### Pathways affected {#pathways}

NCF4 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cross-presentation of particulate exogenous antigens (phagosomes)](https://reactome.org/content/detail/R-HSA-1236973) | curated |
| [Detoxification of Reactive Oxygen Species](https://reactome.org/content/detail/R-HSA-3299685) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHO GTPases Activate NADPH Oxidases](https://reactome.org/content/detail/R-HSA-5668599) | curated |
| [ROS and RNS production in phagocytes](https://reactome.org/content/detail/R-HSA-1222556) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |

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

**Molecular function:** superoxide-generating NADPH oxidase activator activity, phosphatidylinositol-3-phosphate binding.

**Biological process:** superoxide anion generation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-01-24.

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

**Submission history:** 2 submissions (2021–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-24 |

## Associated conditions {#conditions}

[granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3](https://sugi.bio/atlas/disease/granulomatous-disease-chronic-autosomal-recessive-cytochrome-b-positive-type-3/).

**Reported phenotype names (ClinVar):** Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3, not specified, GRANULOMATOUS DISEASE, CHRONIC, DUE TO NCF4 DEFICIENCY, Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type III, GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 3, CGD, AUTOSOMAL RECESSIVE CYTOCHROME b-POSITIVE, TYPE III, AllHighlyPenetrant.

## Similar variants {#similar}

Related NCF4 variant pages (same residue, condition, or type): [NCF4 p.Pro137=](/variant/ncf4-p-pro137), [NCF4 c.118-1G>A](/variant/ncf4-c-118-minus-1g-a), [NCF4 c.759-40C>T](/variant/ncf4-c-759-minus-40c-t), [NCF4 p.Arg105Gln](/variant/ncf4-p-arg105gln), [NCF4 c.758+24C>T](/variant/ncf4-c-758-plus-24c-t), [NCF4 c.758+32G>A](/variant/ncf4-c-758-plus-32g-a), [NCF4 c.758+39T>A](/variant/ncf4-c-758-plus-39t-a), [NCF4 c.758+51G>A](/variant/ncf4-c-758-plus-51g-a).

### 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 1384830). 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.*