# NM_001018115.3(FANCD2):c.1143C>T (p.Asp381=)

https://sugi.bio/variant/fancd2-p-asp381

## Summary

**FANCD2 p.Asp381= (c.1143C>T)** is classified **Likely benign** in FANCD2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-01). Rare (popmax 0.115%, mid); Associated with Fanconi anemia complementation group A.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs376349741 · 7 submitters · 3 linked conditions · rare (popmax 0.115%, mid)

## For patients & families {#patients}

This is a change in the FANCD2 gene that is classified as likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to Fanconi anemia complementation group A.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015170/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.Asp381= |
| Coding change (HGVS c.) | c.1143C>T |
| MANE Select transcript | [NM_001018115](https://www.ncbi.nlm.nih.gov/nuccore/NM_001018115) |
| dbSNP | [rs376349741](https://www.ncbi.nlm.nih.gov/snp/rs376349741/) |
| Variant type | single nucleotide variant |
| Location | chr3:10046588-10046588 (GRCh38) |
| ClinVar | [VCV695992](https://www.ncbi.nlm.nih.gov/clinvar/variation/695992/) |

**All HGVS expressions:** `LRG_306:g.25160C>T`, `LRG_306t2:c.1143C>T`, `NC_000003.11:g.10088272C>T`, `NC_000003.12:g.10046588C>T`, `NG_007311.1:g.25160C>T`, `NG_046754.1:g.15742C>T`, `NM_001018115.2:c.1143C>T`, `NM_001018115.3:c.1143C>T`, `NM_001319984.2:c.1143C>T`, `NM_001374253.1:c.1143C>T`, `NM_001374254.1:c.1143C>T`, `NM_033084.6:c.1143C>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 0.053, GERP -0.294, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.571**. 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>G, Δ0.37 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 **0.115%** (mid) · FAF95 0.0542% · FAF99 0.0422% · 7/6,062 in the highest group · 246/1,614,154 alleles overall — rare (popmax 0.115%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.115% | 866 |
| African / African-American | 0.0613% | 1,632 |
| Admixed American | 0.0566% | 1,766 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,465 |
| European (non-Finnish) | 0.012% | 8,310 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,023 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **381** lies in 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.


### 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-01.

**Submitter consensus:** unanimous (7/7 Likely benign).

**Submission history:** 7 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-30 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-23 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-04-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-11 |

## Associated conditions {#conditions}

[Fanconi anemia complementation group A](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-a/), [Fanconi anemia complementation group D2](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-d2/), [Fanconi anemia](https://sugi.bio/atlas/disease/fanconi-anemia/).

**Reported phenotype names (ClinVar):** Fanconi anemia complementation group A, Fanconi anemia, not provided, not specified, Fanconi anemia complementation group D2, FANCD2-related disorder, FANCD2-related condition, none provided, FANCA-Related Fanconi Anemia, Fanconi anemia, group A.

## Similar variants {#similar}

Related FANCD2 variant pages (same residue, condition, or type): [FANCD2 c.1279-1G>A](/variant/fancd2-c-1279-minus-1g-a), [FANCD2 c.1279-2A>G](/variant/fancd2-c-1279-minus-2a-g), [FANCD2 c.1948-16T>G](/variant/fancd2-c-1948-minus-16t-g), [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).

### 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 695992). 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.*