# NM_001386135.1(AFF3):c.692_693delinsGA (p.Pro231Arg)

https://sugi.bio/variant/aff3-p-pro231arg

## Summary

**AFF3 p.Pro231Arg (c.692_693delinsGA)** is classified **Pathogenic** in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). No gnomAD frequency available for this variant; Associated with AFF3-related neurodevelopmental disorders.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2104735114 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AFF3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to AFF3-related neurodevelopmental disorders.

*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 | [AFF3](https://sugi.bio/atlas/gene/AFF3/) |
| Protein change (HGVS p.) | p.Pro231Arg |
| Coding change (HGVS c.) | c.692_693delinsGA |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| dbSNP | [rs2104735114](https://www.ncbi.nlm.nih.gov/snp/rs2104735114/) |
| Variant type | Indel |
| Location | chr2:100006812-100006813 (GRCh38) |
| ClinVar | [VCV1338773](https://www.ncbi.nlm.nih.gov/clinvar/variation/1338773/) |

**All HGVS expressions:** `NC_000002.11:g.100623274_100623275delinsTC`, `NC_000002.12:g.100006812_100006813delinsTC`, `NG_052835.1:g.140771_140772delinsGA`, `NM_001025108.2:c.767_768delCGinsGA`, `NM_001025108.2:c.767_768delinsGA`, `NM_001386135.1:c.692_693delinsGA`, `NM_002285.3:c.692_693delinsGA`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -5.763, GERP -3.89 — fast-evolving / accelerated position
- Regional missense constraint: **o/e 0.00** across the covering region of the MANE Select transcript (100,006,788–100,006,823), spanning 35 bp — the region is depleted of missense variation. Chi-square p 1.9e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**AFF3** population constraint: LOEUF 0.318, pLI 1, missense-Z 2.2654. *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 **231** lies in the 'disordered' region; a UniProt-annotated variant site (in kins).

AlphaFold model confidence (whole protein): pLDDT 52.20, 15% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-28.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-30 |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2022-04-28 |

## Associated conditions {#conditions}

[AFF3-related neurodevelopmental disorders](https://sugi.bio/atlas/disease/aff3-related-neurodevelopmental-disorders/), [KINSSHIP syndrome](https://sugi.bio/atlas/disease/kinsship-syndrome/).

**Reported phenotype names (ClinVar):** AFF3-related neurodevelopmental disorders, KINSSHIP syndrome, MESOMELIC DYSPLASIA, STEICHEN-GERSDORF TYPE, MESOMELIC DYSPLASIA, AFF3-RELATED.

## Same-residue context {#hotspot}

Residue **231** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [AFF3 p.Pro231Ser](/variant/aff3-p-pro231ser), [AFF3 p.Pro231Leu](/variant/aff3-p-pro231leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AFF3 variant pages (same residue, condition, or type): [AFF3 p.Pro231Leu](/variant/aff3-p-pro231leu), [AFF3 p.Pro231Ser](/variant/aff3-p-pro231ser), [AFF3 p.Thr594_Ala596delinsSer](/variant/aff3-p-thr594-ala596delinsser), [AFF3 p.Ala233Thr](/variant/aff3-p-ala233thr), [AFF3 p.Ala233Val](/variant/aff3-p-ala233val), [AFF3 p.Leu370Phe](/variant/aff3-p-leu370phe), [AFF3 p.Ser222Thr](/variant/aff3-p-ser222thr), [AFF3 p.Met238Arg](/variant/aff3-p-met238arg).

### 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 1338773). 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.*