# NM_199242.3(UNC13D):c.1820G>C (p.Arg607Pro)

https://sugi.bio/variant/unc13d-p-arg607pro

## Summary

**UNC13D p.Arg607Pro (c.1820G>C)** is classified **Conflicting classifications of pathogenicity** in UNC13D (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.9867); Ultra-rare (popmax 0.0459%, nfe); Associated with UNC13D-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs377293829 · 7 submitters · 4 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0459%, nfe)

## For patients & families {#patients}

This is a change in the UNC13D gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to UNC13D-related disorder.

*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.*

**Support & next steps:** [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.Arg607Pro |
| Coding change (HGVS c.) | c.1820G>C |
| MANE Select transcript | [NM_199242](https://www.ncbi.nlm.nih.gov/nuccore/NM_199242) |
| dbSNP | [rs377293829](https://www.ncbi.nlm.nih.gov/snp/rs377293829/) |
| Variant type | single nucleotide variant |
| Location | chr17:75835437-75835437 (GRCh38) |
| ClinVar | [VCV632290](https://www.ncbi.nlm.nih.gov/clinvar/variation/632290/) |

**All HGVS expressions:** `LRG_122:g.14281G>C`, `LRG_122t1:c.1820G>C`, `NC_000017.10:g.73831518C>G`, `NC_000017.11:g.75835437C>G`, `NG_007266.1:g.14281G>C`, `NM_199242.3:c.1820G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9867)
- REVEL 0.684 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.392 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.523, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in UNC13D (of 6,385 modeled).
- CADD: **PHRED 28.0**. 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 1.01** across the covering region of the MANE Select transcript (75,827,968–75,836,102), spanning 8,134 bp. Chi-square p 0.68. 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, Δ0.89 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 **0.0459%** (nfe) · FAF95 0.0426% · FAF99 0.0414% · 541/1,179,838 in the highest group · 568/1,612,832 alleles overall — ultra-rare (popmax 0.0459%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0459% | 2,181 |
| African / African-American | 0.0213% | 4,691 |
| Middle Eastern | 0.0168% | 5,968 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,806 |
| Admixed American | 0.00167% | 59,976 |
| South Asian | 0.0011% | 91,046 |

*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 **607** lies in the mhd1 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.Arg607Pro falls in the mhd1 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (6 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-11-01 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-31 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-01 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-08-09 |
| Dasa | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-10-04 |

## Associated conditions {#conditions}

[UNC13D-related disorder](https://sugi.bio/atlas/disease/unc13d-related-disorder/), [familial hemophagocytic lymphohistiocytosis 3](https://sugi.bio/atlas/disease/familial-hemophagocytic-lymphohistiocytosis-3/), [hereditary hemophagocytic lymphohistiocytosis](https://sugi.bio/atlas/disease/hereditary-hemophagocytic-lymphohistiocytosis/), [autoinflammatory syndrome](https://sugi.bio/atlas/disease/autoinflammatory-syndrome/).

**Reported phenotype names (ClinVar):** UNC13D-related disorder, Familial hemophagocytic lymphohistiocytosis 3, not provided, Familial hemophagocytic lymphohistiocytosis, Autoinflammatory syndrome, UNC13D-related condition, Hereditary hemophagocytic lymphohistiocytosis, Familial erythrophagocytic lymphohistiocytosis, Familial histiocytic reticulosis, none provided.

## Similar variants {#similar}

Related UNC13D variant pages (same residue, condition, or type): [UNC13D p.Arg607Gln](/variant/unc13d-p-arg607gln), [UNC13D p.Arg607Gly](/variant/unc13d-p-arg607gly), [UNC13D p.Arg607Trp](/variant/unc13d-p-arg607trp), [UNC13D p.Arg607=](/variant/unc13d-p-arg607), [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).

### 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 632290). 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.*