Is FTCD p.Leu499Pro (c.1496T>C) pathogenic?

FTCD p.Leu499Pro (c.1496T>C) is classified Uncertain significance in FTCD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). AlphaMissense: likely pathogenic (0.6013); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with FTCD p.Leu499Pro (c.1496T>C)?

FTCD p.Leu499Pro (c.1496T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FTCD p.Leu499Pro (c.1496T>C) in the general population?

FTCD p.Leu499Pro (c.1496T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FTCD p.Leu499Pro (c.1496T>C)?

AlphaMissense predicts likely pathogenic (score 0.6013) — an in-silico prediction, not a clinical call.

FTCD p.Leu499Pro

c.1496T>C · VCV3517655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6013	likely pathogenic
REVEL	0.37	indeterminate
SaProt	LLR -13.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 19 kb · p 0.00063 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,718 alleles · very rare exomes 0/1,461,568 · genomes 2/152,150 · joint denominator

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.Leu499Pro
Coding: c.1496T>C
MANE Select: NM_206965
Type: single nucleotide variant
Location: chr21:46137282 (GRCh38)
Gene constraint: LOEUF 1.61 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.30
Residue 499: the 'cyclodeaminase/cyclohydrolase' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FTCD p.Leu499= Likely benign ★ same residue
FTCD p.Arg255Ter Pathogenic ★★ same condition
FTCD p.Ala108Thr Uncertain significance ★★ ⚠ same condition
FTCD p.Ala159Val Uncertain significance ★★ ⚠ same condition
FTCD p.Ala352Val Uncertain significance ★★ ⚠ same condition
FTCD p.Ala361Val Uncertain significance ★★ same condition
FTCD p.Ala418Thr Uncertain significance ★★ ⚠ same condition
FTCD p.Ala455Thr Uncertain significance ★★ ⚠ same condition

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-leu499pro (accessed [today's date]).

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