# NM_199242.3(UNC13D):c.305G>C (p.Arg102Pro)

https://sugi.bio/variant/unc13d-p-arg102pro

## Summary

**UNC13D p.Arg102Pro (c.305G>C)** is classified **Uncertain significance** in UNC13D (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-13). AlphaMissense: ambiguous (0.4672); Absent from gnomAD v4.1; Associated with familial hemophagocytic lymphohistiocytosis 3.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the UNC13D gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to familial hemophagocytic lymphohistiocytosis 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 |
| Age of onset (of this condition) | Adolescent, Infancy |
| Prevalence | 1-9 / 100 000 (Sweden) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | UNC13D is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Familial hemophagocytic lymphohistiocytosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thrombocytopenia — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Elevated circulating hepatic transaminase concentration — Very frequent (99-80%)
- Immune dysregulation — Very frequent (99-80%)
- Hypoalbuminemia — Very frequent (99-80%)
- Increased circulating ferritin concentration — Very frequent (99-80%)
- Abnormality of serum cytokine level — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009928/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [UNC13D](https://sugi.bio/atlas/gene/UNC13D/) |
| Protein change (HGVS p.) | p.Arg102Pro |
| Coding change (HGVS c.) | c.305G>C |
| MANE Select transcript | [NM_199242](https://www.ncbi.nlm.nih.gov/nuccore/NM_199242) |
| Variant type | single nucleotide variant |
| Location | chr17:75843030-75843030 (GRCh38) |
| ClinVar | [VCV3630935](https://www.ncbi.nlm.nih.gov/clinvar/variation/3630935/) |

**All HGVS expressions:** `LRG_122:g.6688G>C`, `LRG_122t1:c.305G>C`, `NC_000017.10:g.73839111C>G`, `NC_000017.11:g.75843030C>G`, `NG_007266.1:g.6688G>C`, `NM_199242.3:c.305G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4672) — no call either way
- REVEL 0.081 (moderately benign-leaning)
- SaProt LLR -13.18 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate
- Conservation: phyloP -2.23 — fast-evolving / accelerated position
- CADD: **PHRED 11.98**. 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 0.90** across the covering region of the MANE Select transcript (75,836,359–75,844,337), spanning 7,978 bp. Chi-square p 0.017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.85 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**UNC13D** population constraint: LOEUF 0.923, pLI 4.4142e-31, missense-Z 0.44179. *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):

- **familial hemophagocytic lymphohistiocytosis 3** — Definitive (AR)

## Protein context {#protein}

Residue **102** lies in the c2 1 domain.

AlphaFold model confidence (whole protein): pLDDT 85.04, 63% of residues very-high.

**1 experimental structure(s)** (PDB): [9LA9](https://www.rcsb.org/structure/9LA9).

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

*Describes the biological roles of UNC13D (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:** UNC13D's established molecular role includes small GTPase binding. p.Arg102Pro falls in the c2 1 domain.


### Pathways affected {#pathways}

UNC13D participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** small GTPase binding.

**Biological process:** regulation of mast cell degranulation, positive regulation of exocytosis, positive regulation of regulated secretory pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-13 |

## Associated conditions {#conditions}

[familial hemophagocytic lymphohistiocytosis 3](https://sugi.bio/atlas/disease/familial-hemophagocytic-lymphohistiocytosis-3/).

**Reported phenotype names (ClinVar):** Familial hemophagocytic lymphohistiocytosis 3, UNC13D-Related Familial Hemophagocytic Lymphohistiocytosis (UNC13D-fHLH).

## Similar variants {#similar}

Related UNC13D variant pages (same residue, condition, or type): [UNC13D p.Arg102Gln](/variant/unc13d-p-arg102gln), [UNC13D p.Arg102Trp](/variant/unc13d-p-arg102trp), [UNC13D c.1055+1G>A](/variant/unc13d-c-1055-plus-1g-a), [UNC13D c.118-307G>A](/variant/unc13d-c-118-minus-307g-a), [UNC13D c.118-308C>T](/variant/unc13d-c-118-minus-308c-t), [UNC13D c.1389+1G>A](/variant/unc13d-c-1389-plus-1g-a), [UNC13D c.1596+1G>C](/variant/unc13d-c-1596-plus-1g-c), [UNC13D c.1727+1G>A](/variant/unc13d-c-1727-plus-1g-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 3630935). 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.*