# NM_003332.4(TYROBP):c.16C>T (p.Pro6Ser)

https://sugi.bio/variant/tyrobp-p-pro6ser

## Summary

**TYROBP p.Pro6Ser (c.16C>T)** is classified **Likely benign** in TYROBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.0875); Rare (popmax 0.262%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · rare (popmax 0.262%, sas)

## For patients & families {#patients}

This is a change in the TYROBP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [TYROBP](https://sugi.bio/atlas/gene/TYROBP/) |
| Protein change (HGVS p.) | p.Pro6Ser |
| Coding change (HGVS c.) | c.16C>T |
| MANE Select transcript | [NM_003332](https://www.ncbi.nlm.nih.gov/nuccore/NM_003332) |
| Variant type | single nucleotide variant |
| Location | chr19:35908213-35908213 (GRCh38) |
| ClinVar | [VCV3624662](https://www.ncbi.nlm.nih.gov/clinvar/variation/3624662/) |

**All HGVS expressions:** `LRG_607:g.5072C>T`, `LRG_607t1:c.16C>T`, `NC_000019.10:g.35908213G>A`, `NC_000019.9:g.36399115G>A`, `NG_009304.1:g.5072C>T`, `NM_001173514.2:c.16C>T`, `NM_001173515.2:c.16C>T`, `NM_003332.4:c.16C>T`, `NM_198125.3:c.16C>T`, `NR_033390.2:n.83C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0875)
- REVEL 0.176 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.549 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.965, GERP -1.78, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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 1.06** across the covering region of the MANE Select transcript (35,904,572–35,908,228), spanning 3,656 bp. Chi-square p 0.43. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.262%** (sas) · FAF95 0.235% · FAF99 0.224% · 239/91,082 in the highest group · 256/1,614,012 alleles overall — rare (popmax 0.262%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.262% | 381 |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,807 |
| Admixed American | 0.00333% | 30,000 |
| African / African-American | 0.00267% | 37,522 |

*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}

**TYROBP** population constraint: LOEUF 1.274, pLI 7.5496e-05, missense-Z -0.10981; 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.10, 14% of residues very-high.

**5 experimental structure(s)** (PDB): [2L34](https://www.rcsb.org/structure/2L34), [2L35](https://www.rcsb.org/structure/2L35), [4WO1](https://www.rcsb.org/structure/4WO1), [4WOL](https://www.rcsb.org/structure/4WOL), [7Q5W](https://www.rcsb.org/structure/7Q5W).

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

*Describes the biological roles of TYROBP (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:** TYROBP's established molecular role includes signaling receptor binding.


### Pathways affected {#pathways}

TYROBP participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Other semaphorin interactions](https://reactome.org/content/detail/R-HSA-416700) | curated |
| [Signal regulatory protein family interactions](https://reactome.org/content/detail/R-HSA-391160) | curated |
| [DAP12 interactions](https://reactome.org/content/detail/R-HSA-2172127) | electronic |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | electronic |

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

**Molecular function:** signaling receptor binding, protein-macromolecule adaptor activity, identical protein binding, protein homodimerization activity, molecular adaptor activity.

**Biological process:** stimulatory killer cell immunoglobulin-like receptor signaling pathway, stimulatory C-type lectin receptor signaling pathway, natural killer cell mediated immunity, myeloid leukocyte activation, osteoclast differentiation, negative regulation of B cell proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-09.

**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 | 2025-09-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TYROBP variant pages (same residue, condition, or type): [TYROBP p.Ala44Thr](/variant/tyrobp-p-ala44thr), [TYROBP p.Arg70Trp](/variant/tyrobp-p-arg70trp), [TYROBP p.Asp104Asn](/variant/tyrobp-p-asp104asn), [TYROBP p.Asp32Asn](/variant/tyrobp-p-asp32asn), [TYROBP p.Pro40Leu](/variant/tyrobp-p-pro40leu), [TYROBP p.Ser99Leu](/variant/tyrobp-p-ser99leu), [TYROBP p.Val38Met](/variant/tyrobp-p-val38met), [TYROBP p.Val42Met](/variant/tyrobp-p-val42met).

### 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 3624662). 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.*