Is FTCD p.Val99Ala (c.296T>C) pathogenic?

FTCD p.Val99Ala (c.296T>C) is classified Conflicting classifications of pathogenicity in FTCD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1779); Low-frequency (popmax 1.17%, mid); Associated with formiminoglutamic aciduria.

What condition is associated with FTCD p.Val99Ala (c.296T>C)?

FTCD p.Val99Ala (c.296T>C) is associated with formiminoglutamic aciduria (ClinVar).

How common is FTCD p.Val99Ala (c.296T>C) in the general population?

FTCD p.Val99Ala (c.296T>C) is low-frequency (popmax 1.17%, mid) (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.Val99Ala (c.296T>C)?

AlphaMissense predicts likely benign (score 0.1779) — an in-silico prediction, not a clinical call.

FTCD p.Val99Ala

c.296T>C · rs374097903 · VCV393153

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1779 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.17%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

formiminoglutamic aciduria

Computational evidence

Protein change
AlphaMissense	0.1779	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 19 kb · p 0.00063 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.17% Middle Eastern · 70/5,966 alleles

Filtering AF 0.952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.872%

Overall 0.0235% 365/1,553,964 alleles · low-frequency exomes 332/1,401,694 · genomes 33/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.17%	85
Ashkenazi Jewishnot grpmax-eligible	0.286%	349
Remaining individualsnot grpmax-eligible	0.0531%	1,883
Admixed American	0.0175%	5,704
European (non-Finnish)	0.0143%	7,005
South Asian	0.00355%	28,137
Finnishnot grpmax-eligible	0.00342%	29,242
African / African-American	0.00272%	36,781
East Asian	0.0024%	41,616

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.Val99Ala
Coding: c.296T>C
MANE Select: NM_206965
dbSNP: rs374097903
Type: single nucleotide variant
Location: chr21:46152978 (GRCh38)
Gene constraint: LOEUF 1.61 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.30
Residue 99: 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.Val99fs Pathogenic/Likely pathogenic ★★ same residue
FTCD p.Val99Ile Uncertain significance ★ ⚠ 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

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-val99ala (accessed [today's date]).

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