# NM_001099434.2(DCDC2B):c.418G>A (p.Val140Ile)

https://sugi.bio/variant/dcdc2b-p-val140ile

## Summary

**DCDC2B p.Val140Ile (c.418G>A)** is classified **Uncertain significance** in DCDC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0825%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0825%, mid)

## For patients & families {#patients}

This is a change in the DCDC2B 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 | [DCDC2B](https://sugi.bio/atlas/gene/DCDC2B/) |
| Protein change (HGVS p.) | p.Val140Ile |
| Coding change (HGVS c.) | c.418G>A |
| MANE Select transcript | [NM_001099434](https://www.ncbi.nlm.nih.gov/nuccore/NM_001099434) |
| Variant type | single nucleotide variant |
| Location | chr1:32212092-32212092 (GRCh38) |
| ClinVar | [VCV3271042](https://www.ncbi.nlm.nih.gov/clinvar/variation/3271042/) |

**All HGVS expressions:** `NC_000001.10:g.32677693G>A`, `NC_000001.11:g.32212092G>A`, `NM_001099434.2:c.418G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0827)
- REVEL 0.157 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.222 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.066, GERP -4, phastCons 0.004 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 16.3**. 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 1.06** across the covering region of the MANE Select transcript (32,209,094–32,215,894), spanning 6,800 bp. Chi-square p 0.21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.04**, acceptor gain **0.38**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0825%** (mid) · FAF95 0.0324% · FAF99 0.021% · 5/6,058 in the highest group · 15/1,613,800 alleles overall — ultra-rare (popmax 0.0825%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0825% | 1,212 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,004 |
| East Asian | 0.00223% | 44,880 |
| African / African-American | 0.00133% | 75,032 |
| European (non-Finnish) | 0.000509% | 196,626 |

*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}

**DCDC2B** population constraint: LOEUF 1.383, pLI 1.0159e-15, missense-Z -0.28449. *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 **140** lies in the doublecortin 2 domain.

AlphaFold model confidence (whole protein): pLDDT 68.12, 12% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-28.

**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 | 2024-05-28 |

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

## Similar variants {#similar}

Related DCDC2B variant pages (same residue, condition, or type): [DCDC2B p.Ala125Pro](/variant/dcdc2b-p-ala125pro), [DCDC2B p.Ala187Gly](/variant/dcdc2b-p-ala187gly), [DCDC2B p.Ala239Ser](/variant/dcdc2b-p-ala239ser), [DCDC2B p.Ala291Thr](/variant/dcdc2b-p-ala291thr), [DCDC2B p.Ala346Val](/variant/dcdc2b-p-ala346val), [DCDC2B p.Ala55Ser](/variant/dcdc2b-p-ala55ser), [DCDC2B p.Ala55Val](/variant/dcdc2b-p-ala55val), [DCDC2B p.Ala69Glu](/variant/dcdc2b-p-ala69glu).

### 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 3271042). 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.*