Is TKFC p.Val200Ile (c.598G>A) pathogenic?

TKFC p.Val200Ile (c.598G>A) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.086); Ultra-rare (popmax 0.0725%, sas); Associated with triokinase and FMN cyclase deficiency syndrome.

What condition is associated with TKFC p.Val200Ile (c.598G>A)?

TKFC p.Val200Ile (c.598G>A) is associated with triokinase and FMN cyclase deficiency syndrome (ClinVar).

How common is TKFC p.Val200Ile (c.598G>A) in the general population?

TKFC p.Val200Ile (c.598G>A) is ultra-rare (popmax 0.0725%, sas) (gnomAD).

What do computational predictors say about TKFC p.Val200Ile (c.598G>A)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

TKFC p.Val200Ile

c.598G>A · VCV3336659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

triokinase and FMN cyclase deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0725% South Asian · 66/91,082 alleles

Filtering AF 0.0584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00768% 124/1,613,932 alleles · ultra-rare exomes 109/1,461,738 · genomes 15/152,194 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0725%	1,380
Middle Eastern	0.0165%	6,060
Admixed American	0.00833%	12,000
African / African-American	0.00533%	18,746
East Asian	0.00446%	22,444
European (non-Finnish)	0.00381%	26,220
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: TKFC
Protein: p.Val200Ile
Coding: c.598G>A
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61341855 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 200: the dhak domain

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

Disease context

triokinase and FMN cyclase deficiency syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TKFC p.Arg543Ile Likely pathogenic ★★ same condition
TKFC p.Arg228Gln Uncertain significance ★★ ⚠ same condition
TKFC p.Asp403Asn Uncertain significance ★★ ⚠ same condition
TKFC c.194-13C>T Benign ★★ same condition
TKFC c.775+39A>C Benign ★★ same condition
TKFC p.Ala185Thr Benign ★★ same condition
TKFC p.Thr157= Benign ★★ same condition
TKFC p.Val437= Benign ★★ 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/tkfc-p-val200ile (accessed [today's date]).

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