# NM_002025.4(AFF2):c.1173G>A (p.Gln391=)

https://sugi.bio/variant/aff2-p-gln391

## Summary

**AFF2 p.Gln391= (c.1173G>A)** is classified **Uncertain significance** in AFF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). Ultra-rare (popmax 0.0237%, mid); Associated with FRAXE intellectual disability.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs929635504 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0237%, mid)

## For patients & families {#patients}

This is a change in the AFF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Gln391= |
| Coding change (HGVS c.) | c.1173G>A |
| MANE Select transcript | [NM_002025](https://www.ncbi.nlm.nih.gov/nuccore/NM_002025) |
| dbSNP | [rs929635504](https://www.ncbi.nlm.nih.gov/snp/rs929635504/) |
| Variant type | single nucleotide variant |
| Location | chrX:148837733-148837733 (GRCh38) |
| ClinVar | [VCV489209](https://www.ncbi.nlm.nih.gov/clinvar/variation/489209/) |

**All HGVS expressions:** `NC_000023.10:g.147919257G>A`, `NC_000023.11:g.148837733G>A`, `NG_016313.2:g.342115G>A`, `NM_001169122.2:c.1075-5233G>A`, `NM_001169123.2:c.1161G>A`, `NM_001169124.2:c.1087-5233G>A`, `NM_001169125.2:c.1075-5233G>A`, `NM_001170628.1:c.97-5233G>A`, `NM_002025.4:c.1173G>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 **donor loss** (Δ 0.53) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.178, GERP 1.03, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.8**. 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 **0.00**, donor loss **0.53**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.53**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.56** (loss), gain 0.01 / loss 0.56. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0237%** (mid) · FAF95 0.000254% · FAF99 0.000167% · 1/4,226 in the highest group · 7/1,044,764 alleles overall — ultra-rare (popmax 0.0237%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0237% | 4,226 |
| European (non-Finnish) | 0.000705% | 141,812 |

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

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

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-11 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** FRAXE, not provided, none provided, FRAXE Syndrome, FRAXE intellectual disability, Intellectual disability, X-linked, FRAXE type, Fragile XE syndrome, Intellectual developmental disorder, X-linked 109.

## 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.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), [AFF2 p.Phe114Leu](/variant/aff2-p-phe114leu).

### 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 489209). 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.*