Is FTCD p.Val458del (c.1373_1375del) pathogenic?

FTCD p.Val458del (c.13731375del) is classified Uncertain significance in FTCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-01). Ultra-rare (popmax 0.0181%, mid).

How common is FTCD p.Val458del (c.1373_1375del) in the general population?

FTCD p.Val458del (c.1373_1375del) is ultra-rare (popmax 0.0181%, mid) (gnomAD).

FTCD p.Val458del

c.1373_1375del · rs1456176865 · VCV2573552

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.2	GERP 1.5, phastCons 0.85
Overall
CADD	13.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0181% Middle Eastern · 1/5,520 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00227% 36/1,588,188 alleles · ultra-rare exomes 32/1,436,086 · genomes 4/152,102 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0181%	5,520
African / African-American	0.00535%	18,676
European (non-Finnish)	0.00255%	39,148
Remaining individualsnot grpmax-eligible	0.00162%	61,772

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FTCD
Protein: p.Val458del
Coding: c.1373_1375del
MANE Select: NM_206965
dbSNP: rs1456176865
Type: Deletion
Location: chr21:46138576 (GRCh38)
Gene constraint: LOEUF 1.61 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.30
Residue 458: the 'cyclodeaminase/cyclohydrolase' region

Full FTCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FTCD p.Ala62fs Likely pathogenic ★★ same type
FTCD p.Val344fs Pathogenic/Likely pathogenic ★★ same type
FTCD c.1068_1098+24del Likely pathogenic ★ same type
FTCD c.1443+1del Likely pathogenic ★ same type
FTCD p.Ala361fs Likely pathogenic ★ same type
FTCD p.Arg333fs Likely pathogenic ★ same type
FTCD p.Glu332fs Likely pathogenic ★ same type
FTCD p.Glu431fs Likely pathogenic ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ftcd-p-val458del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown