# NM_001166693.3(AFF1):c.3363C>T (p.Ser1121=)

https://sugi.bio/variant/aff1-p-ser1121

## Summary

**AFF1 p.Ser1121= (c.3363C>T)** is classified **Likely benign** in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-01). Rare (popmax 0.103%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs138900630 · 1 submitter · rare (popmax 0.103%, nfe)

## For patients & families {#patients}

This is a change in the AFF1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [AFF1](https://sugi.bio/atlas/gene/AFF1/) |
| Protein change (HGVS p.) | p.Ser1121= |
| Coding change (HGVS c.) | c.3363C>T |
| MANE Select transcript | [NM_001166693](https://www.ncbi.nlm.nih.gov/nuccore/NM_001166693) |
| dbSNP | [rs138900630](https://www.ncbi.nlm.nih.gov/snp/rs138900630/) |
| Variant type | single nucleotide variant |
| Location | chr4:87134522-87134522 (GRCh38) |
| ClinVar | [VCV2654890](https://www.ncbi.nlm.nih.gov/clinvar/variation/2654890/) |

**All HGVS expressions:** `NC_000004.11:g.88055674C>T`, `NC_000004.12:g.87134522C>T`, `NM_001166693.3:c.3363C>T`, `NM_001313959.2:c.3342C>T`, `NM_001313960.2:c.2256C>T`, `NM_005935.4:c.3339C>T`

## 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 -3.134, GERP -4.83 — fast-evolving / accelerated position
- CADD: **PHRED 4.912**. 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 (C>A, Δ0.34 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 **0.103%** (nfe) · FAF95 0.0983% · FAF99 0.0964% · 1,217/1,179,752 in the highest group · 1,304/1,613,420 alleles overall — rare (popmax 0.103%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.11% | 910 |
| European (non-Finnish) (grpmax) | 0.103% | 969 |
| Remaining individuals (not grpmax-eligible) | 0.0768% | 1,302 |
| African / African-American | 0.0253% | 3,947 |
| Admixed American | 0.02% | 4,998 |
| Middle Eastern | 0.0168% | 5,946 |
| South Asian | 0.0044% | 22,753 |
| East Asian | 0.00223% | 44,858 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,986 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**AFF1** population constraint: LOEUF 0.49, pLI 0.94566, missense-Z 0.53163. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 53.06, 15% of residues very-high.

**1 experimental structure(s)** (PDB): [2LM0](https://www.rcsb.org/structure/2LM0).

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-01 |

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

## Similar variants {#similar}

Related AFF1 variant pages (same residue, condition, or type): [AFF1 c.1191+8C>T](/variant/aff1-c-1191-plus-8c-t), [AFF1 p.Ala40=](/variant/aff1-p-ala40), [AFF1 p.Pro393=](/variant/aff1-p-pro393), [AFF1 p.Ser627Cys](/variant/aff1-p-ser627cys), [AFF1 p.Thr426=](/variant/aff1-p-thr426), [AFF1 p.Val711Ile](/variant/aff1-p-val711ile), [AFF1 p.Ala1047Val](/variant/aff1-p-ala1047val), [AFF1 p.Ala1103Thr](/variant/aff1-p-ala1103thr).

### 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 2654890). 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.*