# NM_001386135.1(AFF3):c.82C>T (p.Arg28Trp)

https://sugi.bio/variant/aff3-p-arg28trp

## Summary

**AFF3 p.Arg28Trp (c.82C>T)** is classified **Likely benign** in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.6786); Very rare (popmax 0.00267%, afr); Associated with KINSSHIP syndrome.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the AFF3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to KINSSHIP syndrome.

*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.Arg28Trp |
| Coding change (HGVS c.) | c.82C>T |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| Variant type | single nucleotide variant |
| Location | chr2:100008904-100008904 (GRCh38) |
| ClinVar | [VCV3393138](https://www.ncbi.nlm.nih.gov/clinvar/variation/3393138/) |

**All HGVS expressions:** `NC_000002.11:g.100625366G>A`, `NC_000002.12:g.100008904G>A`, `NG_052835.1:g.138680C>T`, `NM_001025108.2:c.157C>T`, `NM_001386135.1:c.82C>T`, `NM_002285.3:c.82C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6786)
- REVEL 0.65 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.227 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.648, GERP 1.94, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 1.00** across the covering region of the MANE Select transcript (100,006,824–100,008,931), spanning 2,107 bp. Chi-square p 0.95. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.39 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.0005% · FAF99 0.000366% · 2/74,864 in the highest group · 13/1,613,718 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,432 |
| European (non-Finnish) | 0.000932% | 107,265 |

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

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-19 |

## Associated conditions {#conditions}

[KINSSHIP syndrome](https://sugi.bio/atlas/disease/kinsship-syndrome/).

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

## Similar variants {#similar}

Related AFF3 variant pages (same residue, condition, or type): [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.Thr808Ala](/variant/aff3-p-thr808ala), [AFF3 c.1144-2A>G](/variant/aff3-c-1144-minus-2a-g), [AFF3 c.2466+5G>A](/variant/aff3-c-2466-plus-5g-a), [AFF3 c.53+41939G>A](/variant/aff3-c-53-plus-41939g-a).

### 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 3393138). 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.*