# NM_173602.3(DIP2B):c.1304C>T (p.Pro435Leu)

https://sugi.bio/variant/dip2b-p-pro435leu

## Summary

**DIP2B p.Pro435Leu (c.1304C>T)** is classified **Uncertain significance** in DIP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.9203); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DIP2B 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 | [DIP2B](https://sugi.bio/atlas/gene/DIP2B/) |
| Protein change (HGVS p.) | p.Pro435Leu |
| Coding change (HGVS c.) | c.1304C>T |
| MANE Select transcript | [NM_173602](https://www.ncbi.nlm.nih.gov/nuccore/NM_173602) |
| Variant type | single nucleotide variant |
| Location | chr12:50683235-50683235 (GRCh38) |
| ClinVar | [VCV4240647](https://www.ncbi.nlm.nih.gov/clinvar/variation/4240647/) |

**All HGVS expressions:** `NC_000012.11:g.51077018C>T`, `NC_000012.12:g.50683235C>T`, `NG_021196.1:g.183251C>T`, `NM_173602.3:c.1304C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9203)
- REVEL 0.569 (indeterminate)
- SaProt LLR -12.081 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.632, GERP 2.62, 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 0.79** across the covering region of the MANE Select transcript (50,505,141–50,744,836), spanning 239,695 bp. Chi-square p 4.2e-21. 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, Δ0.91 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DIP2B** population constraint: LOEUF 0.448, pLI 0.9998, missense-Z 4.0735. *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 78.83, 45% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-25 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DIP2B variant pages (same residue, condition, or type): [DIP2B p.Asp501Val](/variant/dip2b-p-asp501val), [DIP2B p.Cys1071Ser](/variant/dip2b-p-cys1071ser), [DIP2B p.His1027Arg](/variant/dip2b-p-his1027arg), [DIP2B p.Ile681Val](/variant/dip2b-p-ile681val), [DIP2B p.Ile968Thr](/variant/dip2b-p-ile968thr), [DIP2B p.Ile994Leu](/variant/dip2b-p-ile994leu), [DIP2B p.Pro244Ala](/variant/dip2b-p-pro244ala), [DIP2B p.Pro513Ser](/variant/dip2b-p-pro513ser).

### 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 4240647). 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.*