# NM_001709.5(BDNF):c.172T>C (p.Ser58Pro)

https://sugi.bio/variant/bdnf-p-ser58pro

## Summary

**BDNF p.Ser58Pro (c.172T>C)** is classified **Uncertain significance** in BDNF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-10). AlphaMissense: likely benign (0.1308); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2538964283 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BDNF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [BDNF](https://sugi.bio/atlas/gene/BDNF/) |
| Protein change (HGVS p.) | p.Ser58Pro |
| Coding change (HGVS c.) | c.172T>C |
| MANE Select transcript | [NM_001709](https://www.ncbi.nlm.nih.gov/nuccore/NM_001709) |
| dbSNP | [rs2538964283](https://www.ncbi.nlm.nih.gov/snp/rs2538964283/) |
| Variant type | single nucleotide variant |
| Location | chr11:27658393-27658393 (GRCh38) |
| ClinVar | [VCV2961667](https://www.ncbi.nlm.nih.gov/clinvar/variation/2961667/) |

**All HGVS expressions:** `NC_000011.10:g.27658393A>G`, `NC_000011.9:g.27679940A>G`, `NG_011794.1:g.68666T>C`, `NG_011794.2:g.68637T>C`, `NM_001143805.1:c.172T>C`, `NM_001143806.1:c.172T>C`, `NM_001143807.2:c.172T>C`, `NM_001143808.2:c.172T>C`, `NM_001143809.2:c.259T>C`, `NM_001143810.2:c.418T>C`, `NM_001143811.2:c.172T>C`, `NM_001143812.2:c.172T>C`, `NM_001143813.2:c.172T>C`, `NM_001143814.2:c.172T>C`, `NM_001143816.2:c.172T>C`, `NM_001709.5:c.172T>C`, `NM_170731.5:c.196T>C`, `NM_170732.4:c.172T>C`, `NM_170733.4:c.172T>C`, `NM_170734.4:c.217T>C`, `NM_170735.6:c.172T>C`, `NR_002832.2:n.527A>G`, `NR_033312.1:n.458A>G`, `NR_033313.1:n.458A>G`, `NR_033314.1:n.527A>G`, `NR_033315.1:n.458A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1308)
- REVEL 0.365 (indeterminate)
- SaProt LLR -6.795 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 4.405, GERP -1.6, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 14.58**. 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 0.80** across the covering region of the MANE Select transcript (27,658,189–27,658,564), spanning 375 bp. Chi-square p 0.013. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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}

**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 **58** lies in a functional site (cleavage; by mbtps1).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-10.

**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 | 2023-09-10 |

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

## Similar variants {#similar}

Related BDNF variant pages (same residue, condition, or type): [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), [BDNF p.Thr149=](/variant/bdnf-p-thr149).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2961667). 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.*