# NM_004333.6(BRAF):c.130C>A (p.Pro44Thr)

https://sugi.bio/variant/braf-p-pro44thr

## Summary

**BRAF p.Pro44Thr (c.130C>A)** is classified **Uncertain significance** in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely benign (0.2645); Very rare (popmax 0.000437%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1279627804 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000437%, nfe)

## For patients & families {#patients}

This is a change in the BRAF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [BRAF](https://sugi.bio/atlas/gene/BRAF/) |
| Protein change (HGVS p.) | p.Pro44Thr |
| Coding change (HGVS c.) | c.130C>A |
| MANE Select transcript | [NM_004333](https://www.ncbi.nlm.nih.gov/nuccore/NM_004333) |
| dbSNP | [rs1279627804](https://www.ncbi.nlm.nih.gov/snp/rs1279627804/) |
| Variant type | single nucleotide variant |
| Location | chr7:140924574-140924574 (GRCh38) |
| ClinVar | [VCV2566898](https://www.ncbi.nlm.nih.gov/clinvar/variation/2566898/) |

**All HGVS expressions:** `LRG_299:g.5191C>A`, `LRG_299t1:c.130C>A`, `NC_000007.13:g.140624374G>T`, `NC_000007.14:g.140924574G>T`, `NG_007873.3:g.5191C>A`, `NM_001354609.2:c.130C>A`, `NM_001374244.1:c.130C>A`, `NM_001374258.1:c.130C>A`, `NM_001378467.1:c.130C>A`, `NM_001378468.1:c.130C>A`, `NM_001378469.1:c.130C>A`, `NM_001378470.1:c.130C>A`, `NM_001378471.1:c.130C>A`, `NM_001378474.1:c.130C>A`, `NM_001378475.1:c.130C>A`, `NM_004333.6:c.130C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2645)
- REVEL 0.174 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.924 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 10.567, GERP 2.59, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.7**. 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** — 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 **0.000437%** (nfe) · FAF95 0.000128% · FAF99 9.3e-05% · 5/1,144,150 in the highest group · 5/1,529,630 alleles overall — very rare (popmax 0.000437%, nfe).

*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}

**BRAF** population constraint: LOEUF 0.237, pLI 1, missense-Z 4.9103; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **Noonan syndrome** — Moderate (AD)
- **Noonan syndrome with multiple lentigines** — Limited (AD)
- **cardiofaciocutaneous syndrome** — Definitive (AD)
- **Costello syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **44** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 67.87, 31% of residues very-high.

**135 experimental structure(s)** (PDB): [1UWH](https://www.rcsb.org/structure/1UWH), [1UWJ](https://www.rcsb.org/structure/1UWJ), [2FB8](https://www.rcsb.org/structure/2FB8), [2L05](https://www.rcsb.org/structure/2L05), [3C4C](https://www.rcsb.org/structure/3C4C), [3D4Q](https://www.rcsb.org/structure/3D4Q) — incl. mutant structure 1UWJ.

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

*Describes the biological roles of BRAF (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:** BRAF's established molecular role includes protein kinase activity. In Reactome, BRAF is annotated in disease pathway(s) including **Gain-of-function MRAS complexes activate RAF signaling**, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** BRAF loss or alteration is curated in [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840).

### Pathways affected {#pathways}

BRAF participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [ARMS-mediated activation](https://reactome.org/content/detail/R-HSA-170984) | electronic |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | electronic |
| [Signalling to p38 via RIT and RIN](https://reactome.org/content/detail/R-HSA-187706) | electronic |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, MAP kinase kinase activity, calcium ion binding, identical protein binding, scaffold protein binding.

**Biological process:** MAPK cascade, epidermal growth factor receptor signaling pathway, positive regulation of gene expression, positive regulation of D-glucose transmembrane transport, positive regulation of peptidyl-serine phosphorylation, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-11 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related BRAF variant pages (same residue, condition, or type): [BRAF p.Pro44Leu](/variant/braf-p-pro44leu), [BRAF p.Pro44=](/variant/braf-p-pro44), [BRAF p.Asn236Lys](/variant/braf-p-asn236lys), [BRAF p.Gln262Arg](/variant/braf-p-gln262arg), [BRAF p.Glu501Lys](/variant/braf-p-glu501lys), [BRAF c.2127+4A>G](/variant/braf-c-2127-plus-4a-g), [BRAF p.Ala27Gly](/variant/braf-p-ala27gly), [BRAF p.Ala42Ser](/variant/braf-p-ala42ser).

### 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 2566898). 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.*