# NM_001709.5(BDNF):c.417C>T (p.Ser139=)

https://sugi.bio/variant/bdnf-p-ser139

## Summary

**BDNF p.Ser139= (c.417C>T)** is classified **Likely benign** in BDNF (ClinVar, Single submitter, 2 submitters; last evaluated 2017-09-13). Ultra-rare (popmax 0.012%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs760274076 · 2 submitters · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the BDNF gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [BDNF](https://sugi.bio/atlas/gene/BDNF/) |
| Protein change (HGVS p.) | p.Ser139= |
| Coding change (HGVS c.) | c.417C>T |
| MANE Select transcript | [NM_001709](https://www.ncbi.nlm.nih.gov/nuccore/NM_001709) |
| dbSNP | [rs760274076](https://www.ncbi.nlm.nih.gov/snp/rs760274076/) |
| Variant type | single nucleotide variant |
| Location | chr11:27658148-27658148 (GRCh38) |
| ClinVar | [VCV709884](https://www.ncbi.nlm.nih.gov/clinvar/variation/709884/) |

**All HGVS expressions:** `NC_000011.10:g.27658148G>A`, `NC_000011.9:g.27679695G>A`, `NG_011794.1:g.68911C>T`, `NM_001143805.1:c.417C>T`, `NM_001143806.1:c.417C>T`, `NM_001143807.2:c.417C>T`, `NM_001143808.2:c.417C>T`, `NM_001143809.2:c.504C>T`, `NM_001143810.1:c.663C>T`, `NM_001143810.2:c.663C>T`, `NM_001143811.2:c.417C>T`, `NM_001143812.2:c.417C>T`, `NM_001143813.2:c.417C>T`, `NM_001143814.2:c.417C>T`, `NM_001143816.2:c.417C>T`, `NM_001709.5:c.417C>T`, `NM_170731.5:c.441C>T`, `NM_170732.4:c.417C>T`, `NM_170733.4:c.417C>T`, `NM_170734.4:c.462C>T`, `NM_170735.6:c.417C>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 0.675, GERP -1.45, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 10.41**. 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** — 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 **0.012%** (afr) · FAF95 0.00624% · FAF99 0.00468% · 9/74,878 in the highest group · 35/1,613,940 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.012% | 8,320 |
| Admixed American | 0.005% | 19,999 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |
| East Asian | 0.00223% | 44,888 |
| European (non-Finnish) | 0.00161% | 62,107 |
| South Asian | 0.0011% | 91,074 |

*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}

**BDNF** population constraint: LOEUF 0.233, pLI 0.99974, missense-Z 2.7789. *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 **139** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 71.44, 34% of residues very-high.

**2 experimental structure(s)** (PDB): [1B8M](https://www.rcsb.org/structure/1B8M), [1BND](https://www.rcsb.org/structure/1BND).

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

*Describes the biological roles of BDNF (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:** BDNF participates in disease-associated pathways. In Reactome, BDNF is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** BDNF loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

BDNF participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Activated NTRK2 signals through CDK5](https://reactome.org/content/detail/R-HSA-9032845) | electronic |
| [Activated NTRK2 signals through FRS2 and FRS3](https://reactome.org/content/detail/R-HSA-9028731) | electronic |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | electronic |
| [Activated NTRK2 signals through PI3K](https://reactome.org/content/detail/R-HSA-9028335) | electronic |
| [Activated NTRK2 signals through PLCG1](https://reactome.org/content/detail/R-HSA-9026527) | electronic |
| [Activated NTRK2 signals through RAS](https://reactome.org/content/detail/R-HSA-9026519) | electronic |
| [BDNF activates NTRK2 (TRKB) signaling](https://reactome.org/content/detail/R-HSA-9024909) | electronic |
| [MECP2 regulates transcription of neuronal ligands](https://reactome.org/content/detail/R-HSA-9022702) | electronic |
| [NTRK2 activates RAC1](https://reactome.org/content/detail/R-HSA-9032759) | electronic |

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

**Biological process:** synapse assembly, collateral sprouting, positive regulation of collateral sprouting, positive regulation of synapse assembly.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-09-13.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-09-13 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-11-12 |

**Reported phenotype names (ClinVar):** not provided, BDNF-related disorder, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, BDNF-related condition.

## Similar variants {#similar}

Related BDNF variant pages (same residue, condition, or type): [BDNF p.Ser139Arg](/variant/bdnf-p-ser139arg), [BDNF c.-21-1044G>C](/variant/bdnf-c-minus-21-minus-1044g-c), [BDNF c.-21-1065G>A](/variant/bdnf-c-minus-21-minus-1065g-a), [BDNF c.-21-15778G>T](/variant/bdnf-c-minus-21-minus-15778g-t), [BDNF c.-22+774G>A](/variant/bdnf-c-minus-22-plus-774g-a), [BDNF p.Ala150=](/variant/bdnf-p-ala150), [BDNF p.Asp86=](/variant/bdnf-p-asp86), [BDNF p.Gly161=](/variant/bdnf-p-gly161).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 709884). 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.*