# NM_206965.2(FTCD):c.1545C>T (p.His515=)

https://sugi.bio/variant/ftcd-p-his515

## Summary

**FTCD p.His515= (c.1545C>T)** is classified **Likely benign** in FTCD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). Very rare (popmax 0.00223%, eas); Associated with formiminoglutamic aciduria.

**At a glance:** Likely benign · review: Single submitter · rsID rs1447286926 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the FTCD gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to formiminoglutamic aciduria.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | FTCD is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Formiminoglutamic aciduria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal circulating histidine concentration — Very frequent (99-80%)
- Abnormality of folate metabolism — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Increased blood folate concentration — Frequent (79-30%)
- Abnormal concentration of acylcarnitine in the urine — Frequent (79-30%)
- Delayed speech and language development — Occasional (29-5%)
- Megaloblastic anemia — Occasional (29-5%)
- Anemia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009279/index) · [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.His515= |
| Coding change (HGVS c.) | c.1545C>T |
| MANE Select transcript | [NM_206965](https://www.ncbi.nlm.nih.gov/nuccore/NM_206965) |
| dbSNP | [rs1447286926](https://www.ncbi.nlm.nih.gov/snp/rs1447286926/) |
| Variant type | single nucleotide variant |
| Location | chr21:46137068-46137068 (GRCh38) |
| ClinVar | [VCV1127722](https://www.ncbi.nlm.nih.gov/clinvar/variation/1127722/) |

**All HGVS expressions:** `NC_000021.8:g.47556982G>A`, `NC_000021.9:g.46137068G>A`, `NG_016191.1:g.23500C>T`, `NM_001320412.2:c.1540-15C>T`, `NM_006657.3:c.1545C>T`, `NM_206965.2:c.1545C>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 0.305, GERP 0.178, phastCons 0.011 — weakly conserved position
- CADD: **PHRED 1.531**. 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 (G>C, Δ0.44 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 **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,880 in the highest group · 4/1,613,808 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,880 |
| European (non-Finnish) | 0.000254% | 393,335 |

*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 **515** 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.His515= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-24 |

## Associated conditions {#conditions}

[formiminoglutamic aciduria](https://sugi.bio/atlas/disease/formiminoglutamic-aciduria/).

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

## Same-residue context {#hotspot}

Residue **515** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FTCD p.His515fs](/variant/ftcd-p-his515fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FTCD variant pages (same residue, condition, or type): [FTCD p.His515fs](/variant/ftcd-p-his515fs), [FTCD p.His515Tyr](/variant/ftcd-p-his515tyr), [FTCD p.Arg255Ter](/variant/ftcd-p-arg255ter), [FTCD p.Arg71Ter](/variant/ftcd-p-arg71ter), [FTCD p.Leu536Ter](/variant/ftcd-p-leu536ter), [FTCD p.Ala108Thr](/variant/ftcd-p-ala108thr), [FTCD p.Ala159Val](/variant/ftcd-p-ala159val), [FTCD p.Ala368Val](/variant/ftcd-p-ala368val).

### 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 1127722). 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.*