# NM_206965.2(FTCD):c.1391_1392delinsTG (p.Ala464Val)

https://sugi.bio/variant/ftcd-p-ala464val

## Summary

**FTCD p.Ala464Val (c.1391_1392delinsTG)** is classified **Conflicting classifications of pathogenicity** in FTCD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-06). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2123481486 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FTCD gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Ala464Val |
| Coding change (HGVS c.) | c.1391_1392delinsTG |
| MANE Select transcript | [NM_206965](https://www.ncbi.nlm.nih.gov/nuccore/NM_206965) |
| dbSNP | [rs2123481486](https://www.ncbi.nlm.nih.gov/snp/rs2123481486/) |
| Variant type | Indel |
| Location | chr21:46138559-46138560 (GRCh38) |
| ClinVar | [VCV1443575](https://www.ncbi.nlm.nih.gov/clinvar/variation/1443575/) |

**All HGVS expressions:** `NC_000021.8:g.47558473_47558474delinsCA`, `NC_000021.9:g.46138559_46138560delinsCA`, `NG_016191.1:g.22008_22009delinsTG`, `NM_001320412.2:c.1391_1392delinsTG`, `NM_006657.2:c.1391_1392delCCinsTG`, `NM_006657.3:c.1391_1392delinsTG`, `NM_206965.2:c.1391_1392delinsTG`

## 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 -11.312, GERP -2.7 — fast-evolving / accelerated position
- Regional missense constraint: **o/e 1.12** across the covering region of the MANE Select transcript (46,136,990–46,155,523), spanning 18,533 bp. Chi-square p 0.00063. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **464** 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.Ala464Val 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-06.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2025–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [formiminoglutamic aciduria](https://sugi.bio/atlas/disease/formiminoglutamic-aciduria/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Glutamate formiminotransferase deficiency, Formiminoglutamic aciduria, Arakawa syndrome 1.

## Similar variants {#similar}

Related FTCD variant pages (same residue, condition, or type): [FTCD p.Ala464=](/variant/ftcd-p-ala464), [FTCD p.Ala362fs](/variant/ftcd-p-ala362fs), [FTCD c.969-15_969-14delinsTT](/variant/ftcd-c-969-minus-15-969-minus-14delinstt), [FTCD p.Ala62fs](/variant/ftcd-p-ala62fs), [FTCD p.Arg255Ter](/variant/ftcd-p-arg255ter), [FTCD p.Arg71Ter](/variant/ftcd-p-arg71ter), [FTCD p.Leu536Ter](/variant/ftcd-p-leu536ter), [FTCD p.Pro331fs](/variant/ftcd-p-pro331fs).

### 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 1443575). 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.*