# NM_002025.4(AFF2):c.2656C>G (p.Pro886Ala)

https://sugi.bio/variant/aff2-p-pro886ala

## Summary

**AFF2 p.Pro886Ala (c.2656C>G)** is classified **Benign/Likely benign** in AFF2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1441); Rare (popmax 0.191%, nfe); Associated with FRAXE intellectual disability.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs151043891 · 14 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.191%, nfe)

## For patients & families {#patients}

This is a change in the AFF2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 14 submitters, and is linked to FRAXE intellectual disability.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | AFF2 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of FRAXE intellectual disability** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Agitation — Frequent (79-30%)
- Aggressive behavior — Frequent (79-30%)
- Compulsive behaviors — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Hyperactivity — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Specific learning disability — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002378/index) · [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.Pro886Ala |
| Coding change (HGVS c.) | c.2656C>G |
| MANE Select transcript | [NM_002025](https://www.ncbi.nlm.nih.gov/nuccore/NM_002025) |
| dbSNP | [rs151043891](https://www.ncbi.nlm.nih.gov/snp/rs151043891/) |
| Variant type | single nucleotide variant |
| Location | chrX:148958424-148958424 (GRCh38) |
| ClinVar | [VCV166659](https://www.ncbi.nlm.nih.gov/clinvar/variation/166659/) |

**All HGVS expressions:** `NC_000023.10:g.148039954C>G`, `NC_000023.11:g.148958424C>G`, `NG_016313.2:g.462806C>G`, `NM_001169122.2:c.2557C>G`, `NM_001169123.2:c.2626C>G`, `NM_001169124.2:c.2551C>G`, `NM_001169125.2:c.2539C>G`, `NM_001170628.1:c.1579C>G`, `NM_002025.4:c.2656C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1441)
- REVEL 0.207 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.76 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.488, GERP 1.78, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.1**. 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: **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 **0.191%** (nfe) · FAF95 0.183% · FAF99 0.18% · 1,709/894,776 in the highest group · 1,927/1,209,004 alleles overall — rare (popmax 0.191%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.191% | 524 |
| Admixed American | 0.182% | 550 |
| Remaining individuals (not grpmax-eligible) | 0.132% | 755 |
| Finnish (not grpmax-eligible) | 0.125% | 802 |
| African / African-American | 0.0246% | 4,073 |

*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 **886** lies in the 'disordered' region.

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

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-25.

**Submitter consensus:** conflicting (10 Likely benign, 3 Benign).

**Submission history:** 17 submissions (2014–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-04-10 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-01-15 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-21 |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2017-12-08 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-10 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-03 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Likely benign | no assertion criteria provided | clinical testing | 2019-01-01 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Likely benign | criteria provided, single submitter | clinical testing | 2019-04-17 |

## Associated conditions {#conditions}

[FRAXE intellectual disability](https://sugi.bio/atlas/disease/fraxe-intellectual-disability/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/).

**Reported phenotype names (ClinVar):** FRAXE, not specified, not provided, Intellectual disability, AFF2-related disorder, Thyroid cancer, nonmedullary, 1, Malignant tumor of esophagus, AFF2-related condition, 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.Arg1238Cys](/variant/aff2-p-arg1238cys), [AFF2 p.Arg670His](/variant/aff2-p-arg670his), [AFF2 p.Gln391=](/variant/aff2-p-gln391), [AFF2 p.Glu489Asp](/variant/aff2-p-glu489asp), [AFF2 p.Glu872Gln](/variant/aff2-p-glu872gln), [AFF2 p.Leu610Phe](/variant/aff2-p-leu610phe), [AFF2 p.Leu614Phe](/variant/aff2-p-leu614phe).

### 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 166659). 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.*