# NM_032271.3(TRAF7):c.723G>A (p.Pro241=)

https://sugi.bio/variant/traf7-p-pro241

## Summary

**TRAF7 p.Pro241= (c.723G>A)** is classified **Likely benign** in TRAF7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-07). Rare (popmax 0.184%, sas); Associated with TRAF7-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs564325600 · 1 submitter · 1 linked condition · rare (popmax 0.184%, sas)

## For patients & families {#patients}

This is a change in the TRAF7 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to TRAF7-related disorder.

*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 | [TRAF7](https://sugi.bio/atlas/gene/TRAF7/) |
| Protein change (HGVS p.) | p.Pro241= |
| Coding change (HGVS c.) | c.723G>A |
| MANE Select transcript | [NM_032271](https://www.ncbi.nlm.nih.gov/nuccore/NM_032271) |
| dbSNP | [rs564325600](https://www.ncbi.nlm.nih.gov/snp/rs564325600/) |
| Variant type | single nucleotide variant |
| Location | chr16:2172528-2172528 (GRCh38) |
| ClinVar | [VCV3043714](https://www.ncbi.nlm.nih.gov/clinvar/variation/3043714/) |

**All HGVS expressions:** `NC_000016.10:g.2172528G>A`, `NC_000016.9:g.2222529G>A`, `NM_032271.3:c.723G>A`

## 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 -7.673, GERP -3.83 — fast-evolving / accelerated position
- CADD: **PHRED 6.494**. 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 (G>T, Δ0.49 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 **0.184%** (sas) · FAF95 0.161% · FAF99 0.152% · 162/87,998 in the highest group · 233/1,591,756 alleles overall — rare (popmax 0.184%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.184% | 543 |
| Middle Eastern | 0.0383% | 2,612 |
| Remaining individuals (not grpmax-eligible) | 0.0195% | 5,135 |
| European (non-Finnish) | 0.00479% | 20,889 |
| East Asian | 0.00227% | 44,032 |

*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}

**TRAF7** population constraint: LOEUF 0.675, pLI 1.7117e-06, missense-Z 2.7873; 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):

- **syndromic complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.16, 52% of residues very-high.

**1 experimental structure(s)** (PDB): [8IMS](https://www.rcsb.org/structure/8IMS).

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

*Describes the biological roles of TRAF7 (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:** TRAF7's established molecular role includes ubiquitin-protein transferase activity.


### Pathways affected {#pathways}

TRAF7 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |

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

**Molecular function:** ubiquitin-protein transferase activity, ubiquitin protein ligase activity.

**Biological process:** apoptotic process, protein ubiquitination, protein K29-linked ubiquitination, positive regulation of MAPK cascade, regulation of ERK1 and ERK2 cascade, positive regulation of ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-06-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-07 |

## Associated conditions {#conditions}

[TRAF7-related disorder](https://sugi.bio/atlas/disease/traf7-related-disorder/).

**Reported phenotype names (ClinVar):** TRAF7-related disorder, TRAF7-related condition.

## Similar variants {#similar}

Related TRAF7 variant pages (same residue, condition, or type): [TRAF7 p.Pro241Gln](/variant/traf7-p-pro241gln), [TRAF7 p.Pro241Leu](/variant/traf7-p-pro241leu), [TRAF7 p.Arg524Trp](/variant/traf7-p-arg524trp), [TRAF7 p.Arg655Gln](/variant/traf7-p-arg655gln), [TRAF7 p.Leu625Phe](/variant/traf7-p-leu625phe), [TRAF7 p.Phe617Ser](/variant/traf7-p-phe617ser), [TRAF7 p.Ser663Thr](/variant/traf7-p-ser663thr), [TRAF7 c.1346+3G>A](/variant/traf7-c-1346-plus-3g-a).

### 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 3043714). 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.*