# NM_013232.4(PDCD6):c.105C>T (p.Val35=)

https://sugi.bio/variant/pdcd6-p-val35

## Summary

**PDCD6 p.Val35= (c.105C>T)** is classified **Likely benign** in PDCD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). Rare (popmax 0.117%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs145036962 · 1 submitter · rare (popmax 0.117%, nfe)

## For patients & families {#patients}

This is a change in the PDCD6 gene that is classified as likely benign — not considered disease-causing, 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 | [PDCD6](https://sugi.bio/atlas/gene/PDCD6/) |
| Protein change (HGVS p.) | p.Val35= |
| Coding change (HGVS c.) | c.105C>T |
| MANE Select transcript | [NM_013232](https://www.ncbi.nlm.nih.gov/nuccore/NM_013232) |
| dbSNP | [rs145036962](https://www.ncbi.nlm.nih.gov/snp/rs145036962/) |
| Variant type | single nucleotide variant |
| Location | chr5:272714-272714 (GRCh38) |
| ClinVar | [VCV2655242](https://www.ncbi.nlm.nih.gov/clinvar/variation/2655242/) |

**All HGVS expressions:** `NC_000005.10:g.272714C>T`, `NC_000005.9:g.272829C>T`, `NM_001267556.2:c.105C>T`, `NM_001267557.2:c.105C>T`, `NM_001267558.2:c.-106C>T`, `NM_001267559.2:c.105C>T`, `NM_013232.4:c.105C>T`, `NR_073609.2:n.180C>T`, `NR_165159.2:n.180C>T`, `NR_165163.2:n.180C>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 -0.76, GERP -3.11, phastCons 0.02 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.023**. 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, Δ0.24 acceptor 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 (gnomAD v4.1): grpmax **0.117%** (nfe) · FAF95 0.111% · FAF99 0.109% · 1,355/1,161,056 in the highest group · 1,664/1,574,744 alleles overall — rare (popmax 0.117%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.316% | 317 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.133% | 753 |
| European (non-Finnish) (grpmax) | 0.117% | 857 |
| Remaining individuals (not grpmax-eligible) | 0.102% | 977 |
| Admixed American | 0.00713% | 14,027 |
| African / African-American | 0.00463% | 21,593 |
| East Asian | 0.00225% | 44,376 |
| South Asian | 0.00112% | 89,408 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PDCD6** population constraint: LOEUF 0.847, pLI 0.17294, missense-Z 0.52199. *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 **35** lies in the ef-hand 1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.08, 83% of residues very-high.

**10 experimental structure(s)** (PDB): [2ZN8](https://www.rcsb.org/structure/2ZN8), [2ZN9](https://www.rcsb.org/structure/2ZN9), [2ZND](https://www.rcsb.org/structure/2ZND), [2ZNE](https://www.rcsb.org/structure/2ZNE), [2ZRS](https://www.rcsb.org/structure/2ZRS), [2ZRT](https://www.rcsb.org/structure/2ZRT).

## What this gene does {#gene-function}

*Describes the biological roles of PDCD6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PDCD6's established molecular role includes calcium ion binding. p.Val35= falls in the ef-hand 1 domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium ion binding, protein-macromolecule adaptor activity, identical protein binding, protein homodimerization activity, protein-membrane adaptor activity, protein heterodimerization activity.

**Biological process:** positive regulation of endothelial cell proliferation, intracellular protein transport, endoplasmic reticulum to Golgi vesicle-mediated transport, positive regulation of endothelial cell migration, neural crest formation, neural crest cell development.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-02-01 |

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

## Similar variants {#similar}

Related PDCD6 variant pages (same residue, condition, or type): [PDCD6 p.Ala118Thr](/variant/pdcd6-p-ala118thr), [PDCD6 p.Arg100Cys](/variant/pdcd6-p-arg100cys), [PDCD6 p.Arg125Trp](/variant/pdcd6-p-arg125trp), [PDCD6 p.Arg136Gln](/variant/pdcd6-p-arg136gln), [PDCD6 p.Asn54Lys](/variant/pdcd6-p-asn54lys), [PDCD6 p.Asn54Ser](/variant/pdcd6-p-asn54ser), [PDCD6 p.Asp139Gly](/variant/pdcd6-p-asp139gly), [PDCD6 p.Cys155Phe](/variant/pdcd6-p-cys155phe).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2655242). 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.*