# NM_001018115.3(FANCD2):c.288T>C (p.Phe96=)

https://sugi.bio/variant/fancd2-p-phe96

## Summary

**FANCD2 p.Phe96= (c.288T>C)** is classified **Likely benign** in FANCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-03). No allele count reported in gnomAD v4.1 (AN 1,565,656); Associated with Fanconi anemia.

**At a glance:** Likely benign · review: Single submitter · rsID rs2124975093 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,565,656)

## For patients & families {#patients}

This is a change in the FANCD2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Fanconi anemia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 85 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FANCD2 is a diagnostic-grade gene on 18 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006425/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FANCD2](https://sugi.bio/atlas/gene/FANCD2/) |
| Protein change (HGVS p.) | p.Phe96= |
| Coding change (HGVS c.) | c.288T>C |
| MANE Select transcript | [NM_001018115](https://www.ncbi.nlm.nih.gov/nuccore/NM_001018115) |
| dbSNP | [rs2124975093](https://www.ncbi.nlm.nih.gov/snp/rs2124975093/) |
| Variant type | single nucleotide variant |
| Location | chr3:10034709-10034709 (GRCh38) |
| ClinVar | [VCV2732749](https://www.ncbi.nlm.nih.gov/clinvar/variation/2732749/) |

**All HGVS expressions:** `LRG_306:g.13281T>C`, `LRG_306t1:c.288T>C`, `LRG_306t2:c.288T>C`, `NC_000003.11:g.10076393T>C`, `NC_000003.12:g.10034709T>C`, `NG_007311.1:g.13281T>C`, `NG_046754.1:g.3863T>C`, `NM_001018115.3:c.288T>C`, `NM_001319984.2:c.288T>C`, `NM_001374253.1:c.288T>C`, `NM_001374254.1:c.288T>C`, `NM_001374255.1:c.288T>C`, `NM_033084.6:c.288T>C`

## 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 0.246, GERP 0.666, phastCons 0.601 — weakly conserved position
- CADD: **PHRED 9.647**. 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 (T>A, Δ0.23 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: **no allele count reported in gnomAD v4.1 (AN 1,565,656)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**FANCD2** population constraint: LOEUF 0.777, pLI 2.7719e-19, missense-Z 1.7648; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Fanconi anemia complementation group D2** — Definitive (AR)

## Protein context {#protein}

Residue **96** lies in the 'interaction with fance' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 77.24, 33% of residues very-high.

**13 experimental structure(s)** (PDB): [6VAA](https://www.rcsb.org/structure/6VAA), [6VAD](https://www.rcsb.org/structure/6VAD), [6VAE](https://www.rcsb.org/structure/6VAE), [6VAF](https://www.rcsb.org/structure/6VAF), [7AY1](https://www.rcsb.org/structure/7AY1), [7KZQ](https://www.rcsb.org/structure/7KZQ).

## What this gene does {#gene-function}

*Describes the biological roles of FANCD2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FANCD2's established molecular role includes DNA polymerase binding. p.Phe96= falls in the interaction with fance region.


### Pathways affected {#pathways}

FANCD2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Fanconi Anemia Pathway](https://reactome.org/content/detail/R-HSA-6783310) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA polymerase binding.

**Biological process:** response to gamma radiation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-03 |

## Associated conditions {#conditions}

[Fanconi anemia](https://sugi.bio/atlas/disease/fanconi-anemia/).

**Reported phenotype names (ClinVar):** Fanconi anemia, Fanconi's anemia.

## Similar variants {#similar}

Related FANCD2 variant pages (same residue, condition, or type): [FANCD2 p.Phe96Leu](/variant/fancd2-p-phe96leu), [FANCD2 c.1948-6C>A](/variant/fancd2-c-1948-minus-6c-a), [FANCD2 c.206-1G>T](/variant/fancd2-c-206-minus-1g-t), [FANCD2 c.2169-1G>C](/variant/fancd2-c-2169-minus-1g-c), [FANCD2 c.2269+1G>A](/variant/fancd2-c-2269-plus-1g-a), [FANCD2 c.2715+1G>A](/variant/fancd2-c-2715-plus-1g-a), [FANCD2 c.3224+1G>T](/variant/fancd2-c-3224-plus-1g-t), [FANCD2 c.3467-2A>G](/variant/fancd2-c-3467-minus-2a-g).

### 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 2732749). 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.*