Is FTCD p.Ser12Leu (c.35C>T) pathogenic?

FTCD p.Ser12Leu (c.35C>T) is classified Uncertain significance in FTCD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely pathogenic (0.8891); Very rare (popmax 0.00933%, afr); Associated with formiminoglutamic aciduria.

What condition is associated with FTCD p.Ser12Leu (c.35C>T)?

FTCD p.Ser12Leu (c.35C>T) is associated with formiminoglutamic aciduria (ClinVar).

How common is FTCD p.Ser12Leu (c.35C>T) in the general population?

FTCD p.Ser12Leu (c.35C>T) is very rare (popmax 0.00933%, afr) (gnomAD).

How is Formiminoglutamic aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FTCD p.Ser12Leu (c.35C>T)?

AlphaMissense predicts likely pathogenic (score 0.8891) — an in-silico prediction, not a clinical call.

FTCD p.Ser12Leu

c.35C>T · rs201753824 · VCV529459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

formiminoglutamic aciduria

Computational evidence

Protein change
AlphaMissense	0.8891	likely pathogenic · top 10% in FTCD
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -13.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 19 kb · p 0.00063 · regional, not allelic
Overall
CADD	32.0	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 0.00933% African / African-American · 7/75,046 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00155% 25/1,612,874 alleles · very rare exomes 18/1,460,556 · genomes 7/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,721
South Asian	0.00549%	18,216
East Asian	0.00223%	44,882
European (non-Finnish)	0.00102%	98,317

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.Ser12Leu
Coding: c.35C>T
MANE Select: NM_206965
dbSNP: rs201753824
Type: single nucleotide variant
Location: chr21:46155489 (GRCh38)
Gene constraint: LOEUF 1.61 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.30
Residue 12: the 'formiminotransferase n-subdomain' region

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

Disease context

formiminoglutamic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Formiminoglutamic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

FTCD p.Ser12= Benign ★ same residue
FTCD p.Arg255Ter Pathogenic ★★ same condition
FTCD p.Arg71Ter Pathogenic/Likely pathogenic ★★ same condition
FTCD p.Leu536Ter Pathogenic/Likely pathogenic ★★ same condition
FTCD p.Ala108Thr Uncertain significance ★★ ⚠ same condition
FTCD p.Ala159Val Uncertain significance ★★ ⚠ same condition
FTCD p.Ala368Val Uncertain significance ★★ ⚠ same condition
FTCD p.Ala418Thr 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-ser12leu (accessed [today's date]).

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