# NM_206965.2(FTCD):c.1373_1375del (p.Val458del)

https://sugi.bio/variant/ftcd-p-val458del

## Summary

**FTCD p.Val458del (c.1373_1375del)** is classified **Uncertain significance** in FTCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-01). Ultra-rare (popmax 0.0181%, mid).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1456176865 · 2 submitters · ultra-rare (popmax 0.0181%, mid)

## For patients & families {#patients}

This is a change in the FTCD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [FTCD](https://sugi.bio/atlas/gene/FTCD/) |
| Protein change (HGVS p.) | p.Val458del |
| Coding change (HGVS c.) | c.1373_1375del |
| MANE Select transcript | [NM_206965](https://www.ncbi.nlm.nih.gov/nuccore/NM_206965) |
| dbSNP | [rs1456176865](https://www.ncbi.nlm.nih.gov/snp/rs1456176865/) |
| Variant type | Deletion |
| Location | chr21:46138576-46138578 (GRCh38) |
| ClinVar | [VCV2573552](https://www.ncbi.nlm.nih.gov/clinvar/variation/2573552/) |

**All HGVS expressions:** `NC_000021.8:g.47558492_47558494del`, `NC_000021.9:g.46138578_46138580del`, `NG_016191.1:g.21990_21992del`, `NM_001320412.2:c.1373_1375del`, `NM_006657.2:c.1373_1375del`, `NM_006657.2:c.1373_1375delTGG`, `NM_006657.3:c.1373_1375del`, `NM_206965.2:c.1373_1375del`

## 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 4.217, GERP 1.48, phastCons 0.853 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 13.21**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0181%** (mid) · FAF95 0.00181% · FAF99 0.00157% · 1/5,520 in the highest group · 36/1,588,188 alleles overall — ultra-rare (popmax 0.0181%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0181% | 5,520 |
| African / African-American | 0.00535% | 18,676 |
| European (non-Finnish) | 0.00255% | 39,148 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,772 |

*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}

**FTCD** population constraint: LOEUF 1.61, pLI 1.2895e-29, missense-Z -2.0472; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **458** lies in the 'cyclodeaminase/cyclohydrolase' region.

AlphaFold model confidence (whole protein): pLDDT 95.30, 91% of residues very-high.

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

*Describes the biological roles of FTCD (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:** FTCD's established molecular role includes microtubule binding. p.Val458del falls in the cyclodeaminase/cyclohydrolase region.


### Pathways affected {#pathways}

FTCD participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Histidine catabolism](https://reactome.org/content/detail/R-HSA-70921) | curated |

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

**Molecular function:** microtubule binding, glutamate formimidoyltransferase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-01.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-27 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-01 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related FTCD variant pages (same residue, condition, or type): [FTCD p.Ala62fs](/variant/ftcd-p-ala62fs), [FTCD p.Val344fs](/variant/ftcd-p-val344fs), [FTCD c.1068_1098+24del](/variant/ftcd-c-1068-1098-plus-24del), [FTCD c.1443+1del](/variant/ftcd-c-1443-plus-1del), [FTCD p.Ala361fs](/variant/ftcd-p-ala361fs), [FTCD p.Arg333fs](/variant/ftcd-p-arg333fs), [FTCD p.Glu332fs](/variant/ftcd-p-glu332fs), [FTCD p.Glu431fs](/variant/ftcd-p-glu431fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2573552). 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.*