# NM_015151.4(DIP2A):c.1919C>T (p.Pro640Leu)

https://sugi.bio/variant/dip2a-p-pro640leu

## Summary

**DIP2A p.Pro640Leu (c.1919C>T)** is classified **Uncertain significance** in DIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-11). AlphaMissense: likely pathogenic (0.9533); Very rare (popmax 0.00972%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs776089050 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00972%, amr)

## 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.

*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.Pro640Leu |
| Coding change (HGVS c.) | c.1919C>T |
| MANE Select transcript | [NM_015151](https://www.ncbi.nlm.nih.gov/nuccore/NM_015151) |
| dbSNP | [rs776089050](https://www.ncbi.nlm.nih.gov/snp/rs776089050/) |
| Variant type | single nucleotide variant |
| Location | chr21:46538600-46538600 (GRCh38) |
| ClinVar | [VCV2688931](https://www.ncbi.nlm.nih.gov/clinvar/variation/2688931/) |

**All HGVS expressions:** `NC_000021.8:g.47958513C>T`, `NC_000021.9:g.46538600C>T`, `NG_015996.1:g.84652C>T`, `NG_015996.2:g.84711C>T`, `NM_001146115.2:c.1790C>T`, `NM_001146116.2:c.1907C>T`, `NM_001353942.2:c.1922C>T`, `NM_001353943.2:c.1919C>T`, `NM_001353944.2:c.1670C>T`, `NM_001410751.1:c.1919C>T`, `NM_015151.4:c.1919C>T`, `NM_206889.3:c.1919C>T`, `NM_206890.3:c.1919C>T`, `NM_206891.3:c.1919C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9533)
- REVEL 0.576 (indeterminate)
- SaProt LLR -8.107 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.664, GERP 1.92, phastCons 1 — highly conserved (agrees)
- 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 0.85** 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>G, Δ0.52 donor 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 **0.00972%** (amr) · FAF95 0.0038% · FAF99 0.00246% · 5/51,432 in the highest group · 21/1,550,886 alleles overall — very rare (popmax 0.00972%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00972% | 10,286 |
| Remaining individuals (not grpmax-eligible) | 0.00332% | 30,124 |
| East Asian | 0.00243% | 41,132 |
| African / African-American | 0.00137% | 73,194 |
| South Asian | 0.00119% | 84,138 |
| European (non-Finnish) | 0.000957% | 104,455 |

*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 Single submitter *(criteria provided, single submitter)*, last evaluated 2019-10-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-10-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DIP2A variant pages (same residue, condition, or type): [DIP2A p.Ala676Thr](/variant/dip2a-p-ala676thr), [DIP2A p.Glu832Lys](/variant/dip2a-p-glu832lys), [DIP2A p.Pro333=](/variant/dip2a-p-pro333), [DIP2A p.Pro798Leu](/variant/dip2a-p-pro798leu), [DIP2A p.Thr848=](/variant/dip2a-p-thr848), [DIP2A p.Val1531=](/variant/dip2a-p-val1531), [DIP2A c.1429+2T>G](/variant/dip2a-c-1429-plus-2t-g), [DIP2A c.2395-2A>G](/variant/dip2a-c-2395-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 2688931). 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.*