# NM_003824.4(FADD):c.12C>T (p.Phe4=)

https://sugi.bio/variant/fadd-p-phe4

## Summary

**FADD p.Phe4= (c.12C>T)** is classified **Likely benign** in FADD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). Very rare (popmax 0.00464%, eas); Associated with FADD-related immunodeficiency.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00464%, eas)

## For patients & families {#patients}

This is a change in the FADD gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to FADD-related immunodeficiency.

*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) | Infancy, Neonatal |
| Diagnostic panels | FADD is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of FADD-related immunodeficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Obligate (100%)
- Encephalopathy — Obligate (100%)
- Decreased liver function — Obligate (100%)
- Hepatic fibrosis — Frequent (79-30%)
- Cerebral atrophy — Frequent (79-30%)
- Ventricular septal defect — Occasional (29-5%)
- Pulmonary artery atresia — Occasional (29-5%)
- Autoimmune antibody positivity — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015004/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FADD](https://sugi.bio/atlas/gene/FADD/) |
| Protein change (HGVS p.) | p.Phe4= |
| Coding change (HGVS c.) | c.12C>T |
| MANE Select transcript | [NM_003824](https://www.ncbi.nlm.nih.gov/nuccore/NM_003824) |
| Variant type | single nucleotide variant |
| Location | chr11:70203471-70203471 (GRCh38) |
| ClinVar | [VCV3716151](https://www.ncbi.nlm.nih.gov/clinvar/variation/3716151/) |

**All HGVS expressions:** `LRG_228:g.5309C>T`, `LRG_228t1:c.12C>T`, `NC_000011.10:g.70203471C>T`, `NC_000011.9:g.70049577C>T`, `NG_027966.1:g.5309C>T`, `NM_003824.4:c.12C>T`

## 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 0.302, GERP 0.54, phastCons 0.989 — weakly conserved position
- CADD: **PHRED 11.87**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00464%** (eas) · FAF95 0.000768% · FAF99 0.000287% · 2/43,140 in the highest group · 5/1,584,324 alleles overall — very rare (popmax 0.00464%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00464% | 21,570 |
| African / African-American | 0.00135% | 74,258 |
| European (non-Finnish) | 0.000172% | 582,795 |

*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}

**FADD** population constraint: LOEUF 1.715, pLI 0.069433, missense-Z 0.66783; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **FADD-related immunodeficiency** — Moderate (AR)

## Protein context {#protein}

Residue **4** lies in the ded domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 72.60, 0% of residues very-high.

**18 experimental structure(s)** (PDB): [1A1W](https://www.rcsb.org/structure/1A1W), [1A1Z](https://www.rcsb.org/structure/1A1Z), [1E3Y](https://www.rcsb.org/structure/1E3Y), [1E41](https://www.rcsb.org/structure/1E41), [2GF5](https://www.rcsb.org/structure/2GF5), [3EZQ](https://www.rcsb.org/structure/3EZQ) — incl. mutant structure 1A1W.

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

*Describes the biological roles of FADD (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:** FADD's established molecular role includes protease binding. p.Phe4= falls in the ded domain. In Reactome, FADD is annotated in disease pathway(s) including **Defective RIPK1-mediated regulated necrosis**.

**Disease mechanism (Reactome):** FADD loss or alteration is curated in [Defective RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9693928).

### Pathways affected {#pathways}

FADD participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-9693928) | curated |
| [CASP8 activity is inhibited](https://reactome.org/content/detail/R-HSA-5218900) | curated |
| [Caspase activation via Death Receptors in the presence of ligand](https://reactome.org/content/detail/R-HSA-140534) | curated |
| [Dimerization of procaspase-8](https://reactome.org/content/detail/R-HSA-69416) | curated |
| [FasL/ CD95L signaling](https://reactome.org/content/detail/R-HSA-75157) | curated |
| [NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10](https://reactome.org/content/detail/R-HSA-933543) | curated |
| [RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-5213460) | curated |
| [Regulation by c-FLIP](https://reactome.org/content/detail/R-HSA-3371378) | curated |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [Regulation of necroptotic cell death](https://reactome.org/content/detail/R-HSA-5675482) | curated |
| [TLR3-mediated TICAM1-dependent programmed cell death](https://reactome.org/content/detail/R-HSA-9013957) | curated |
| [TNFR1-induced proapoptotic signaling](https://reactome.org/content/detail/R-HSA-5357786) | curated |
| [TRAIL  signaling](https://reactome.org/content/detail/R-HSA-75158) | curated |
| [TRIF-mediated programmed cell death](https://reactome.org/content/detail/R-HSA-2562578) | curated |

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

**Molecular function:** protease binding, protein-macromolecule adaptor activity, tumor necrosis factor receptor superfamily binding, death effector domain binding, identical protein binding, caspase binding.

**Biological process:** apoptotic process, extrinsic apoptotic signaling pathway via death domain receptors, positive regulation of interleukin-8 production, positive regulation of tumor necrosis factor production, TRAIL-activated apoptotic signaling pathway, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-26.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[FADD-related immunodeficiency](https://sugi.bio/atlas/disease/fadd-related-immunodeficiency/).

**Reported phenotype names (ClinVar):** FADD-related immunodeficiency, FADD DEFICIENCY, Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformations.

## Similar variants {#similar}

Related FADD variant pages (same residue, condition, or type): [FADD p.Ala156Thr](/variant/fadd-p-ala156thr), [FADD p.Asp106Asn](/variant/fadd-p-asp106asn), [FADD p.Ile126Met](/variant/fadd-p-ile126met), [FADD p.Met193Thr](/variant/fadd-p-met193thr), [FADD p.Ser18Arg](/variant/fadd-p-ser18arg), [FADD p.Thr151Ile](/variant/fadd-p-thr151ile), [FADD p.Val103Ile](/variant/fadd-p-val103ile), [FADD c.286+20G>A](/variant/fadd-c-286-plus-20g-a).

### 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 3716151). 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.*