# NM_000594.4(TNF):c.251C>T (p.Pro84Leu)

https://sugi.bio/variant/tnf-p-pro84leu

## Summary

**TNF p.Pro84Leu (c.251C>T)** is classified **Benign/Likely benign** in TNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.082); Low-frequency (popmax 1.81%, mid).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs4645843 · 2 submitters · AlphaMissense likely benign · low-frequency (popmax 1.81%, mid)

## For patients & families {#patients}

This is a change in the TNF gene that is classified as benign/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 | [TNF](https://sugi.bio/atlas/gene/TNF/) |
| Protein change (HGVS p.) | p.Pro84Leu |
| Coding change (HGVS c.) | c.251C>T |
| MANE Select transcript | [NM_000594](https://www.ncbi.nlm.nih.gov/nuccore/NM_000594) |
| dbSNP | [rs4645843](https://www.ncbi.nlm.nih.gov/snp/rs4645843/) |
| Variant type | single nucleotide variant |
| Location | chr6:31576785-31576785 (GRCh38) |
| ClinVar | [VCV781865](https://www.ncbi.nlm.nih.gov/clinvar/variation/781865/) |

**All HGVS expressions:** `NC_000006.11:g.31544562C>T`, `NC_000006.12:g.31576785C>T`, `NG_007462.1:g.6213C>T`, `NM_000594.4:c.251C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.082)
- REVEL 0.188 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.716 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.668, GERP -2.44 — weakly conserved position
- CADD: **PHRED 16.35**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.81%** (mid) · FAF95 1.54% · FAF99 1.44% · 110/6,062 in the highest group · 2,927/1,612,964 alleles overall — low-frequency (popmax 1.81%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 1.81% | 55 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.07% | 94 |
| South Asian | 0.441% | 227 |
| Remaining individuals (not grpmax-eligible) | 0.282% | 355 |
| Admixed American | 0.277% | 361 |
| European (non-Finnish) | 0.144% | 695 |
| African / African-American | 0.06% | 1,667 |
| Finnish (not grpmax-eligible) | 0.0175% | 5,722 |
| East Asian | 0.00446% | 22,440 |

*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}

**TNF** population constraint: LOEUF 0.592, pLI 0.8577, missense-Z 1.9262. *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 **84** lies in a UniProt-annotated variant site (in); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.72, 63% of residues very-high.

**52 experimental structure(s)** (PDB): [1A8M](https://www.rcsb.org/structure/1A8M), [1TNF](https://www.rcsb.org/structure/1TNF), [21TV](https://www.rcsb.org/structure/21TV), [21TW](https://www.rcsb.org/structure/21TW), [2AZ5](https://www.rcsb.org/structure/2AZ5), [2E7A](https://www.rcsb.org/structure/2E7A) — incl. mutant structure 1A8M.

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

*Describes the biological roles of TNF (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:** TNF's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

TNF participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)](https://reactome.org/content/detail/R-HSA-9942503) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [TNF signaling](https://reactome.org/content/detail/R-HSA-75893) | curated |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | curated |
| [TNFR1-induced proapoptotic signaling](https://reactome.org/content/detail/R-HSA-5357786) | curated |
| [TNFR1-mediated ceramide production](https://reactome.org/content/detail/R-HSA-5626978) | curated |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, protease binding, cytokine activity, tumor necrosis factor receptor binding, identical protein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cytokine production, chronic inflammatory response to antigenic stimulus, negative regulation of cytokine production involved in immune response, inflammatory response, extrinsic apoptotic signaling pathway via death domain receptors.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-07-15 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |

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

## Similar variants {#similar}

Related TNF variant pages (same residue, condition, or type): [TNF p.Arg107Leu](/variant/tnf-p-arg107leu), [TNF p.Asp66Asn](/variant/tnf-p-asp66asn), [TNF p.Gly184Arg](/variant/tnf-p-gly184arg), [TNF p.Gly54Glu](/variant/tnf-p-gly54glu), [TNF p.Gly57Ser](/variant/tnf-p-gly57ser), [TNF p.Met6Lys](/variant/tnf-p-met6lys), [TNF p.Thr83Asn](/variant/tnf-p-thr83asn), [TNF p.Val117Ala](/variant/tnf-p-val117ala).

### 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 781865). 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.*