# NM_001375524.1(TRRAP):c.1194C>T (p.Ala398=)

https://sugi.bio/variant/trrap-p-ala398

## Summary

**TRRAP p.Ala398= (c.1194C>T)** is classified **Likely benign** in TRRAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-29). Ultra-rare (popmax 0.0494%, eas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs537115692 · 2 submitters · ultra-rare (popmax 0.0494%, eas)

## For patients & families {#patients}

This is a change in the TRRAP 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 | [TRRAP](https://sugi.bio/atlas/gene/TRRAP/) |
| Protein change (HGVS p.) | p.Ala398= |
| Coding change (HGVS c.) | c.1194C>T |
| MANE Select transcript | [NM_001375524](https://www.ncbi.nlm.nih.gov/nuccore/NM_001375524) |
| dbSNP | [rs537115692](https://www.ncbi.nlm.nih.gov/snp/rs537115692/) |
| Variant type | single nucleotide variant |
| Location | chr7:98908806-98908806 (GRCh38) |
| ClinVar | [VCV1989405](https://www.ncbi.nlm.nih.gov/clinvar/variation/1989405/) |

**All HGVS expressions:** `NC_000007.13:g.98506429C>T`, `NC_000007.14:g.98908806C>T`, `NG_030010.1:g.35317C>T`, `NM_001244580.2:c.1194C>T`, `NM_001375524.1:c.1194C>T`, `NM_003496.4:c.1194C>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 -20, GERP -3.5 — fast-evolving / accelerated position
- CADD: **PHRED 6.251**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.68 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0494%** (eas) · FAF95 0.0334% · FAF99 0.0281% · 22/44,560 in the highest group · 45/1,606,268 alleles overall — ultra-rare (popmax 0.0494%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0494% | 2,025 |
| Admixed American | 0.017% | 5,887 |
| Middle Eastern | 0.0165% | 6,058 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,250 |
| European (non-Finnish) | 0.000935% | 106,955 |

*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}

**TRRAP** population constraint: LOEUF 0.115, pLI 1, missense-Z 10.527; ClinGen dosage — haploinsufficiency 1/3, 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):

- **complex neurodevelopmental disorder with or without congenital anomalies** — Definitive (AD)

## Protein context {#protein}

Residue **398** lies in an α-helix.

**9 experimental structure(s)** (PDB): [7KTR](https://www.rcsb.org/structure/7KTR), [8H7G](https://www.rcsb.org/structure/8H7G), [8QRI](https://www.rcsb.org/structure/8QRI), [8XVG](https://www.rcsb.org/structure/8XVG), [8XVV](https://www.rcsb.org/structure/8XVV), [9C47](https://www.rcsb.org/structure/9C47).

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

*Describes the biological roles of TRRAP (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:** TRRAP's established molecular role includes transcription coregulator activity.


### Pathways affected {#pathways}

TRRAP participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

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

**Molecular function:** transcription coregulator activity.

**Biological process:** regulation of transcription by RNA polymerase II, regulation of cell cycle, positive regulation of double-strand break repair via homologous recombination.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-29.

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

**Submission history:** 2 submissions (2024–2025); 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 | 2025-01-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-22 |

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

## Similar variants {#similar}

Related TRRAP variant pages (same residue, condition, or type): [TRRAP p.Arg1035Gln](/variant/trrap-p-arg1035gln), [TRRAP p.Glu1104Gly](/variant/trrap-p-glu1104gly), [TRRAP p.Glu1106Lys](/variant/trrap-p-glu1106lys), [TRRAP p.Met3318Val](/variant/trrap-p-met3318val), [TRRAP p.Val1030Ile](/variant/trrap-p-val1030ile), [TRRAP c.2622+3A>G](/variant/trrap-c-2622-plus-3a-g), [TRRAP c.7176+4A>G](/variant/trrap-c-7176-plus-4a-g), [TRRAP c.8247+5G>T](/variant/trrap-c-8247-plus-5g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1989405). 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.*