# NM_002025.4(AFF2):c.2601G>A (p.Lys867=)

https://sugi.bio/variant/aff2-p-lys867

## Summary

**AFF2 p.Lys867= (c.2601G>A)** is classified **Likely benign** in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-01). Very rare (popmax 0.00223%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs185675988 · 2 submitters · very rare (popmax 0.00223%, nfe)

## For patients & families {#patients}

This is a change in the AFF2 gene that is classified as 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 | [AFF2](https://sugi.bio/atlas/gene/AFF2/) |
| Protein change (HGVS p.) | p.Lys867= |
| Coding change (HGVS c.) | c.2601G>A |
| MANE Select transcript | [NM_002025](https://www.ncbi.nlm.nih.gov/nuccore/NM_002025) |
| dbSNP | [rs185675988](https://www.ncbi.nlm.nih.gov/snp/rs185675988/) |
| Variant type | single nucleotide variant |
| Location | chrX:148958369-148958369 (GRCh38) |
| ClinVar | [VCV2661610](https://www.ncbi.nlm.nih.gov/clinvar/variation/2661610/) |

**All HGVS expressions:** `NC_000023.10:g.148039899G>A`, `NC_000023.11:g.148958369G>A`, `NG_016313.2:g.462751G>A`, `NM_001169122.2:c.2502G>A`, `NM_001169123.2:c.2571G>A`, `NM_001169124.2:c.2496G>A`, `NM_001169125.2:c.2484G>A`, `NM_001170628.1:c.1524G>A`, `NM_002025.4:c.2601G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.347, GERP 1.78, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 6.833**. 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 deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (nfe) · FAF95 0.00146% · FAF99 0.00119% · 20/894,915 in the highest group · 20/1,209,493 alleles overall — very rare (popmax 0.00223%, 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}

**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 **867** 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-02-18 |

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

## Similar variants {#similar}

Related AFF2 variant pages (same residue, condition, or type): [AFF2 c.3267+5G>C](/variant/aff2-c-3267-plus-5g-c), [AFF2 p.Ala1197Thr](/variant/aff2-p-ala1197thr), [AFF2 p.Ala171Pro](/variant/aff2-p-ala171pro), [AFF2 p.Arg1238Cys](/variant/aff2-p-arg1238cys), [AFF2 p.Arg1295Cys](/variant/aff2-p-arg1295cys), [AFF2 p.Arg670His](/variant/aff2-p-arg670his), [AFF2 p.Asn77Ile](/variant/aff2-p-asn77ile), [AFF2 p.Asp187Glu](/variant/aff2-p-asp187glu).

### 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 2661610). 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.*