# NM_005879.3(TRAIP):c.663G>T (p.Val221=)

https://sugi.bio/variant/traip-p-val221

## Summary

**TRAIP p.Val221= (c.663G>T)** is classified **Likely benign** in TRAIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). Very rare (popmax 0.00167%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the TRAIP 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 | [TRAIP](https://sugi.bio/atlas/gene/TRAIP/) |
| Protein change (HGVS p.) | p.Val221= |
| Coding change (HGVS c.) | c.663G>T |
| MANE Select transcript | [NM_005879](https://www.ncbi.nlm.nih.gov/nuccore/NM_005879) |
| Variant type | single nucleotide variant |
| Location | chr3:49841027-49841027 (GRCh38) |
| ClinVar | [VCV3683780](https://www.ncbi.nlm.nih.gov/clinvar/variation/3683780/) |

**All HGVS expressions:** `NC_000003.11:g.49878460C>A`, `NC_000003.12:g.49841027C>A`, `NG_046695.1:g.20533G>T`, `NM_005879.3:c.663G>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 0.285, GERP -2.82, phastCons 0.891 — weakly conserved position
- CADD: **PHRED 6.819**. 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>T, Δ0.21 acceptor loss), 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 **0.00167%** (amr) · 1/60,020 in the highest group · 1/1,461,880 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**TRAIP** population constraint: LOEUF 0.739, pLI 1.7835e-06, missense-Z 1.8702. *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 **221** lies in the 'interaction with cyld' region.

AlphaFold model confidence (whole protein): pLDDT 75.24, 48% of residues very-high.

**1 experimental structure(s)** (PDB): [4ZTD](https://www.rcsb.org/structure/4ZTD).

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

*Describes the biological roles of TRAIP (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:** TRAIP's established molecular role includes ubiquitin-protein transferase activity. p.Val221= falls in the interaction with cyld region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | other |

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

**Molecular function:** ubiquitin-protein transferase activity, identical protein binding.

**Biological process:** DNA damage response, negative regulation of tumor necrosis factor-mediated signaling pathway, protein ubiquitination, replication fork processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-13 |

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

## Similar variants {#similar}

Related TRAIP variant pages (same residue, condition, or type): [TRAIP p.Arg436Cys](/variant/traip-p-arg436cys), [TRAIP p.Arg436His](/variant/traip-p-arg436his), [TRAIP p.Asp244His](/variant/traip-p-asp244his), [TRAIP p.Asp431Gly](/variant/traip-p-asp431gly), [TRAIP p.Gln36Arg](/variant/traip-p-gln36arg), [TRAIP p.Glu209Lys](/variant/traip-p-glu209lys), [TRAIP p.Gly421Ser](/variant/traip-p-gly421ser), [TRAIP p.Ile104Met](/variant/traip-p-ile104met).

### 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 3683780). 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.*