# NM_014423.4(AFF4):c.2519C>T (p.Ser840Phe)

https://sugi.bio/variant/aff4-p-ser840phe

## Summary

**AFF4 p.Ser840Phe (c.2519C>T)** is classified **Uncertain significance** in AFF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely benign (0.1771); Very rare (popmax 0.000254%, nfe); Associated with AFF4-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the AFF4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to AFF4-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 | [AFF4](https://sugi.bio/atlas/gene/AFF4/) |
| Protein change (HGVS p.) | p.Ser840Phe |
| Coding change (HGVS c.) | c.2519C>T |
| MANE Select transcript | [NM_014423](https://www.ncbi.nlm.nih.gov/nuccore/NM_014423) |
| Variant type | single nucleotide variant |
| Location | chr5:132892282-132892282 (GRCh38) |
| ClinVar | [VCV3354823](https://www.ncbi.nlm.nih.gov/clinvar/variation/3354823/) |

**All HGVS expressions:** `NC_000005.10:g.132892282G>A`, `NC_000005.9:g.132227974G>A`, `NG_030340.1:g.76381C>T`, `NM_014423.4:c.2519C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1771)
- REVEL 0.204 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.472 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.693, GERP 4.82, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.5**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (132,889,080–132,896,615), spanning 7,535 bp. Chi-square p 0.44. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,042 in the highest group · 3/1,613,936 alleles overall — very rare (popmax 0.000254%, 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}

**AFF4** population constraint: LOEUF 0.114, pLI 1, missense-Z 3.6501. *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 **840** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 54.62, 18% of residues very-high.

**9 experimental structure(s)** (PDB): [4IMY](https://www.rcsb.org/structure/4IMY), [4OGR](https://www.rcsb.org/structure/4OGR), [4OR5](https://www.rcsb.org/structure/4OR5), [5JW9](https://www.rcsb.org/structure/5JW9), [5L1Z](https://www.rcsb.org/structure/5L1Z), [6CYT](https://www.rcsb.org/structure/6CYT).

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

*Describes the biological roles of AFF4 (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.*


### Pathways affected {#pathways}

AFF4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-22 |

## Associated conditions {#conditions}

[AFF4-related disorder](https://sugi.bio/atlas/disease/aff4-related-disorder/).

**Reported phenotype names (ClinVar):** AFF4-related disorder, AFF4-related condition.

## Similar variants {#similar}

Related AFF4 variant pages (same residue, condition, or type): [AFF4 p.Glu657Asp](/variant/aff4-p-glu657asp), [AFF4 p.Ser839Cys](/variant/aff4-p-ser839cys), [AFF4 p.Ala551Thr](/variant/aff4-p-ala551thr), [AFF4 p.Arg209Ser](/variant/aff4-p-arg209ser), [AFF4 p.Arg725Lys](/variant/aff4-p-arg725lys), [AFF4 p.Asp422Gly](/variant/aff4-p-asp422gly), [AFF4 p.Pro611Leu](/variant/aff4-p-pro611leu), [AFF4 p.Ser1077Phe](/variant/aff4-p-ser1077phe).

### 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 3354823). 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.*