# NM_014974.3(DIP2C):c.156G>A (p.Pro52=)

https://sugi.bio/variant/dip2c-p-pro52

## Summary

**DIP2C p.Pro52= (c.156G>A)** is classified **Uncertain significance** in DIP2C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). Ultra-rare (popmax 0.0156%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs753310455 · 1 submitter · ultra-rare (popmax 0.0156%, amr)

## For patients & families {#patients}

This is a change in the DIP2C 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 | [DIP2C](https://sugi.bio/atlas/gene/DIP2C/) |
| Protein change (HGVS p.) | p.Pro52= |
| Coding change (HGVS c.) | c.156G>A |
| MANE Select transcript | [NM_014974](https://www.ncbi.nlm.nih.gov/nuccore/NM_014974) |
| dbSNP | [rs753310455](https://www.ncbi.nlm.nih.gov/snp/rs753310455/) |
| Variant type | single nucleotide variant |
| Location | chr10:486460-486460 (GRCh38) |
| ClinVar | [VCV2077020](https://www.ncbi.nlm.nih.gov/clinvar/variation/2077020/) |

**All HGVS expressions:** `NC_000010.10:g.532400C>T`, `NC_000010.11:g.486460C>T`, `NM_014974.3:c.156G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.34) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.648, GERP -3.68, phastCons 0.021 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.075**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.34**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0156%** (amr) · FAF95 0.00812% · FAF99 0.006% · 9/57,622 in the highest group · 14/1,598,098 alleles overall — ultra-rare (popmax 0.0156%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0156% | 6,402 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,754 |
| African / African-American | 0.00135% | 74,164 |
| European (non-Finnish) | 0.000256% | 390,877 |

*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}

**DIP2C** population constraint: LOEUF 0.235, pLI 1, missense-Z 4.7898. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **52** lies in the dmap1-binding domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 79.64, 48% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-27 |

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

## Similar variants {#similar}

Related DIP2C variant pages (same residue, condition, or type): [DIP2C p.Pro52Leu](/variant/dip2c-p-pro52leu), [DIP2C p.Ala1066Thr](/variant/dip2c-p-ala1066thr), [DIP2C p.Ala1066Val](/variant/dip2c-p-ala1066val), [DIP2C p.Ala1101Val](/variant/dip2c-p-ala1101val), [DIP2C p.Ala1155Thr](/variant/dip2c-p-ala1155thr), [DIP2C p.Ala1466Thr](/variant/dip2c-p-ala1466thr), [DIP2C p.Ala193Val](/variant/dip2c-p-ala193val), [DIP2C p.Ala422Thr](/variant/dip2c-p-ala422thr).

### 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 2077020). 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.*