# NM_015151.4(DIP2A):c.2544C>T (p.Thr848=)

https://sugi.bio/variant/dip2a-p-thr848

## Summary

**DIP2A p.Thr848= (c.2544C>T)** is classified **Benign/Likely benign** in DIP2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). Low-frequency (popmax 1.01%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs143909470 · 3 submitters · low-frequency (popmax 1.01%, afr)

## For patients & families {#patients}

This is a change in the DIP2A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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.Thr848= |
| Coding change (HGVS c.) | c.2544C>T |
| MANE Select transcript | [NM_015151](https://www.ncbi.nlm.nih.gov/nuccore/NM_015151) |
| dbSNP | [rs143909470](https://www.ncbi.nlm.nih.gov/snp/rs143909470/) |
| Variant type | single nucleotide variant |
| Location | chr21:46549792-46549792 (GRCh38) |
| ClinVar | [VCV708063](https://www.ncbi.nlm.nih.gov/clinvar/variation/708063/) |

**All HGVS expressions:** `NC_000021.8:g.47969705C>T`, `NC_000021.9:g.46549792C>T`, `NG_015996.1:g.95844C>T`, `NM_001146116.2:c.2532C>T`, `NM_001353942.2:c.2547C>T`, `NM_001353943.2:c.2544C>T`, `NM_015151.4:c.2544C>T`, `NM_206889.3:c.2544C>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 -20, GERP -4.16 — fast-evolving / accelerated position
- CADD: **PHRED 0.064**. 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>A, Δ0.26 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 **1.01%** (afr) · FAF95 0.953% · FAF99 0.929% · 760/75,050 in the highest group · 1,063/1,613,792 alleles overall — low-frequency (popmax 1.01%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.01% | 99 |
| Remaining individuals (not grpmax-eligible) | 0.0912% | 1,097 |
| Admixed American | 0.0483% | 2,070 |
| Middle Eastern | 0.033% | 3,031 |
| European (non-Finnish) | 0.0177% | 5,646 |
| South Asian | 0.00439% | 22,772 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| East Asian | 0.00223% | 44,886 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-01-30 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |

**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.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), [DIP2A p.Ala1017Thr](/variant/dip2a-p-ala1017thr).

### 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 708063). 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.*