# NM_015151.4(DIP2A):c.1804C>T (p.Arg602Trp)

https://sugi.bio/variant/dip2a-p-arg602trp

## Summary

**DIP2A p.Arg602Trp (c.1804C>T)** is classified **Uncertain significance** in DIP2A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely benign (0.1934); Very rare (popmax 0.00411%, afr); Associated with DIP2A-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00411%, afr)

## For patients & families {#patients}

This is a change in the DIP2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to DIP2A-related disorder.

*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 | [DIP2A](https://sugi.bio/atlas/gene/DIP2A/) |
| Protein change (HGVS p.) | p.Arg602Trp |
| Coding change (HGVS c.) | c.1804C>T |
| MANE Select transcript | [NM_015151](https://www.ncbi.nlm.nih.gov/nuccore/NM_015151) |
| Variant type | single nucleotide variant |
| Location | chr21:46538485-46538485 (GRCh38) |
| ClinVar | [VCV3353263](https://www.ncbi.nlm.nih.gov/clinvar/variation/3353263/) |

**All HGVS expressions:** `NC_000021.8:g.47958398C>T`, `NC_000021.9:g.46538485C>T`, `NG_015996.1:g.84537C>T`, `NG_015996.2:g.84596C>T`, `NM_001146115.2:c.1675C>T`, `NM_001146116.2:c.1792C>T`, `NM_001353942.2:c.1807C>T`, `NM_001353943.2:c.1804C>T`, `NM_001353944.2:c.1555C>T`, `NM_001410751.1:c.1804C>T`, `NM_015151.4:c.1804C>T`, `NM_206889.3:c.1804C>T`, `NM_206890.3:c.1804C>T`, `NM_206891.3:c.1804C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1934)
- REVEL 0.188 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.118 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 1.061, GERP -1.55, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 26.4**. 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 0.85** across the covering region of the MANE Select transcript (46,459,132–46,567,619), spanning 108,487 bp. Chi-square p 1.5e-11. 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, Δ0.22 acceptor gain), 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 **0.00411%** (afr) · FAF95 0.00109% · FAF99 0.000502% · 3/73,034 in the highest group · 6/1,544,170 alleles overall — very rare (popmax 0.00411%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00411% | 24,345 |
| European (non-Finnish) | 0.000261% | 382,507 |

*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}

**DIP2A** population constraint: LOEUF 0.617, pLI 1.5943e-09, missense-Z 2.22; ClinGen dosage — haploinsufficiency 1, 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.93, 48% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-04-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-04-03 |

## Associated conditions {#conditions}

[DIP2A-related disorder](https://sugi.bio/atlas/disease/dip2a-related-disorder/).

**Reported phenotype names (ClinVar):** DIP2A-related disorder, DIP2A-related condition.

## Similar variants {#similar}

Related DIP2A variant pages (same residue, condition, or type): [DIP2A p.Arg602Gln](/variant/dip2a-p-arg602gln), [DIP2A p.Ala1026Ser](/variant/dip2a-p-ala1026ser), [DIP2A c.2637+25G>T](/variant/dip2a-c-2637-plus-25g-t), [DIP2A p.Ala1260Ser](/variant/dip2a-p-ala1260ser), [DIP2A p.Glu63Asp](/variant/dip2a-p-glu63asp), [DIP2A p.Lys281Thr](/variant/dip2a-p-lys281thr), [DIP2A p.Ser1249Cys](/variant/dip2a-p-ser1249cys), [DIP2A c.1707+7G>A](/variant/dip2a-c-1707-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 3353263). 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.*