# NM_001386135.1(AFF3):c.1003G>C (p.Asp335His)

https://sugi.bio/variant/aff3-p-asp335his

## Summary

**AFF3 p.Asp335His (c.1003G>C)** is classified **Uncertain significance** in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-13). AlphaMissense: ambiguous (0.451); Very rare (popmax 0.00494%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00494%, nfe)

## For patients & families {#patients}

This is a change in the AFF3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [AFF3](https://sugi.bio/atlas/gene/AFF3/) |
| Protein change (HGVS p.) | p.Asp335His |
| Coding change (HGVS c.) | c.1003G>C |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| Variant type | single nucleotide variant |
| Location | chr2:99744140-99744140 (GRCh38) |
| ClinVar | [VCV4853179](https://www.ncbi.nlm.nih.gov/clinvar/variation/4853179/) |

**All HGVS expressions:** `NC_000002.11:g.100360602C>G`, `NC_000002.12:g.99744140C>G`, `NG_052835.1:g.403444G>C`, `NM_001025108.2:c.1078G>C`, `NM_001386135.1:c.1003G>C`, `NM_002285.3:c.1003G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.451) — no call either way
- REVEL 0.322 (indeterminate)
- SaProt LLR -6.797 (tolerated)
- Conservation: phyloP 5.94, GERP 2.62, phastCons 1 — highly conserved
- 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 0.97** across the covering region of the MANE Select transcript (99,593,948–100,006,787), spanning 412,839 bp. Chi-square p 0.58. 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 (C>A, Δ0.39 donor 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 **0.00494%** (nfe) · FAF95 0.00387% · FAF99 0.00354% · 58/1,174,948 in the highest group · 62/1,603,240 alleles overall — very rare (popmax 0.00494%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00494% | 20,258 |
| Remaining individuals (not grpmax-eligible) | 0.00483% | 20,698 |
| Admixed American | 0.00172% | 58,226 |

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

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-05-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-05-13 |

**Reported phenotype names (ClinVar):** not specified, 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 2026-10-11); 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 4853179). 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.*