# NM_001386135.1(AFF3):c.2910C>T (p.Phe970=)

https://sugi.bio/variant/aff3-p-phe970

## Summary

**AFF3 p.Phe970= (c.2910C>T)** is classified **Likely benign** in AFF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-12). Rare (popmax 0.688%, eas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs142157056 · 3 submitters · rare (popmax 0.688%, eas)

## For patients & families {#patients}

This is a change in the AFF3 gene that is classified as likely 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.Phe970= |
| Coding change (HGVS c.) | c.2910C>T |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| dbSNP | [rs142157056](https://www.ncbi.nlm.nih.gov/snp/rs142157056/) |
| Variant type | single nucleotide variant |
| Location | chr2:99578335-99578335 (GRCh38) |
| ClinVar | [VCV3059808](https://www.ncbi.nlm.nih.gov/clinvar/variation/3059808/) |

**All HGVS expressions:** `NC_000002.11:g.100194797G>A`, `NC_000002.12:g.99578335G>A`, `NG_052835.1:g.569249C>T`, `NM_001025108.2:c.2985C>T`, `NM_001386135.1:c.2910C>T`, `NM_002285.3:c.2910C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.815, GERP -0.619, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 6.478**. 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 **0.22**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 8 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.688%** (eas) · FAF95 0.625% · FAF99 0.6% · 303/44,018 in the highest group · 445/1,599,048 alleles overall — rare (popmax 0.688%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.688% | 145 |
| Remaining individuals (not grpmax-eligible) | 0.0581% | 1,721 |
| African / African-American | 0.0432% | 2,314 |
| South Asian | 0.0318% | 3,146 |
| Admixed American | 0.0251% | 3,988 |
| European (non-Finnish) | 0.00272% | 36,717 |

*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}


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

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-12.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-03-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-24 |

**Reported phenotype names (ClinVar):** AFF3-related disorder, not specified, AFF3-related condition, AllHighlyPenetrant.

## 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.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), [AFF3 c.1371+7G>A](/variant/aff3-c-1371-plus-7g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3059808). 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.*