# NM_002025.4(AFF2):c.2687G>A (p.Arg896Lys)

https://sugi.bio/variant/aff2-p-arg896lys

## Summary

**AFF2 p.Arg896Lys (c.2687G>A)** is classified **Likely benign** in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.058); Ultra-rare (popmax 0.0461%, mid); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0461%, mid)

## For patients & families {#patients}

This is a change in the AFF2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [AFF2](https://sugi.bio/atlas/gene/AFF2/) |
| Protein change (HGVS p.) | p.Arg896Lys |
| Coding change (HGVS c.) | c.2687G>A |
| MANE Select transcript | [NM_002025](https://www.ncbi.nlm.nih.gov/nuccore/NM_002025) |
| Variant type | single nucleotide variant |
| Location | chrX:148958455-148958455 (GRCh38) |
| ClinVar | [VCV3503856](https://www.ncbi.nlm.nih.gov/clinvar/variation/3503856/) |

**All HGVS expressions:** `NC_000023.10:g.148039985G>A`, `NC_000023.11:g.148958455G>A`, `NG_016313.2:g.462837G>A`, `NM_001169122.2:c.2588G>A`, `NM_001169123.2:c.2657G>A`, `NM_001169124.2:c.2582G>A`, `NM_001169125.2:c.2570G>A`, `NM_001170628.1:c.1610G>A`, `NM_002025.4:c.2687G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.058)
- REVEL 0.081 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.447 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.411, GERP -1.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 9.189**. 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 0.94** across the covering region of the MANE Select transcript (148,662,608–148,966,994), spanning 304,386 bp. Chi-square p 0.17. 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 **0.01**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.0461%** (mid) · FAF95 0.00815% · FAF99 0.00341% · 2/4,338 in the highest group · 4/1,096,114 alleles overall — ultra-rare (popmax 0.0461%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0461% | 2,169 |
| European (non-Finnish) | 0.000224% | 447,223 |

*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}

**AFF2** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **non-syndromic X-linked intellectual disability** — Definitive (XL)

## Protein context {#protein}

Residue **896** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 49.27, 15% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related AFF2 variant pages (same residue, condition, or type): [AFF2 p.Ala1197Thr](/variant/aff2-p-ala1197thr), [AFF2 p.Arg1295Cys](/variant/aff2-p-arg1295cys), [AFF2 p.Asp187Glu](/variant/aff2-p-asp187glu), [AFF2 p.Gln205Lys](/variant/aff2-p-gln205lys), [AFF2 p.Gly482Arg](/variant/aff2-p-gly482arg), [AFF2 p.Gly740Val](/variant/aff2-p-gly740val), [AFF2 p.His1070Arg](/variant/aff2-p-his1070arg), [AFF2 p.His366Arg](/variant/aff2-p-his366arg).

### 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 3503856). 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.*