# NM_001386135.1(AFF3):c.1188C>T (p.Ala396=)

https://sugi.bio/variant/aff3-p-ala396

## Summary

**AFF3 p.Ala396= (c.1188C>T)** is classified **Benign** in AFF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-08). Common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs4851214 · 3 submitters · common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the AFF3 gene that is classified as benign — not considered disease-causing, submitted by 3 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 | [AFF3](https://sugi.bio/atlas/gene/AFF3/) |
| Protein change (HGVS p.) | p.Ala396= |
| Coding change (HGVS c.) | c.1188C>T |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| dbSNP | [rs4851214](https://www.ncbi.nlm.nih.gov/snp/rs4851214/) |
| Variant type | single nucleotide variant |
| Location | chr2:99601618-99601618 (GRCh38) |
| ClinVar | [VCV1243294](https://www.ncbi.nlm.nih.gov/clinvar/variation/1243294/) |

**All HGVS expressions:** `NC_000002.11:g.100218080G>A`, `NC_000002.12:g.99601618G>A`, `NG_052835.1:g.545966C>T`, `NM_001025108.2:c.1263C>T`, `NM_001386135.1:c.1188C>T`, `NM_002285.3:c.1188C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -1.178, GERP -1.34 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.816**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.59 acceptor gain), 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 **36.7%** (eas) · FAF95 36.2% · FAF99 36% · 16,309/44,492 in the highest group · 434,943/1,590,294 alleles overall — common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 36.7% | 3 |
| South Asian | 34.6% | 3 |
| Middle Eastern | 29.6% | 3 |
| Amish (not grpmax-eligible) | 29.5% | 3 |
| European (non-Finnish) | 28.3% | 4 |
| Remaining individuals (not grpmax-eligible) | 27.3% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 24.8% | 4 |
| Finnish (not grpmax-eligible) | 23% | 4 |
| Admixed American | 22.9% | 4 |
| African / African-American | 4.98% | 20 |

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

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

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-08.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-06-02 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-05-08 |

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

## Similar variants {#similar}

Related AFF3 variant pages (same residue, condition, or type): [AFF3 p.Ala396Thr](/variant/aff3-p-ala396thr), [AFF3 p.Ala233Thr](/variant/aff3-p-ala233thr), [AFF3 p.Ala233Val](/variant/aff3-p-ala233val), [AFF3 p.Ile1147Asn](/variant/aff3-p-ile1147asn), [AFF3 p.Leu370Phe](/variant/aff3-p-leu370phe), [AFF3 p.Pro321Leu](/variant/aff3-p-pro321leu), [AFF3 p.Ser222Thr](/variant/aff3-p-ser222thr), [AFF3 p.Thr950Met](/variant/aff3-p-thr950met).

### 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 1243294). 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.*