# NM_020350.5(AGTRAP):c.81A>G (p.Ser27=)

https://sugi.bio/variant/agtrap-p-ser27

## Summary

**AGTRAP p.Ser27= (c.81A>G)** is classified **Likely benign** in AGTRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). Very rare (popmax 0.00119%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00119%, nfe)

## For patients & families {#patients}

This is a change in the AGTRAP 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 | [AGTRAP](https://sugi.bio/atlas/gene/AGTRAP/) |
| Protein change (HGVS p.) | p.Ser27= |
| Coding change (HGVS c.) | c.81A>G |
| MANE Select transcript | [NM_020350](https://www.ncbi.nlm.nih.gov/nuccore/NM_020350) |
| Variant type | single nucleotide variant |
| Location | chr1:11747458-11747458 (GRCh38) |
| ClinVar | [VCV4025473](https://www.ncbi.nlm.nih.gov/clinvar/variation/4025473/) |

**All HGVS expressions:** `NC_000001.10:g.11807515A>G`, `NC_000001.11:g.11747458A>G`, `NM_001040194.2:c.81A>G`, `NM_001040195.2:c.46A>G`, `NM_001040196.2:c.178A>G`, `NM_001040197.2:c.178A>G`, `NM_020350.5:c.81A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.88) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.337, GERP -2.3 — fast-evolving / accelerated position
- CADD: **PHRED 0.572**. 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 deltas (raw): acceptor loss **0.88**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**. Largest is acceptor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00119%** (nfe) · FAF95 0.000689% · FAF99 0.000539% · 14/1,179,826 in the highest group · 14/1,613,786 alleles overall — very rare (popmax 0.00119%, 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}

**AGTRAP** population constraint: LOEUF 0.838, pLI 0.12563, missense-Z 0.79283. *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 80.97, 60% of residues very-high.

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

*Describes the biological roles of AGTRAP (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:** AGTRAP's established molecular role includes identical protein binding. In Reactome, AGTRAP is annotated in disease pathway(s) including **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** AGTRAP loss or alteration is curated in [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

AGTRAP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |

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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-08 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AGTRAP variant pages (same residue, condition, or type): [AGTRAP p.Arg157Gln](/variant/agtrap-p-arg157gln), [AGTRAP p.Ala53Thr](/variant/agtrap-p-ala53thr), [AGTRAP p.Arg113Cys](/variant/agtrap-p-arg113cys), [AGTRAP p.Arg113His](/variant/agtrap-p-arg113his), [AGTRAP p.Arg130Cys](/variant/agtrap-p-arg130cys), [AGTRAP p.Arg130Ser](/variant/agtrap-p-arg130ser), [AGTRAP p.Arg157Leu](/variant/agtrap-p-arg157leu), [AGTRAP p.Arg48Gln](/variant/agtrap-p-arg48gln).

### 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 4025473). 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.*