Is TKFC p.Arg286Cys (c.856C>T) pathogenic?

TKFC p.Arg286Cys (c.856C>T) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1246); Ultra-rare (popmax 0.0329%, mid); Associated with triokinase and FMN cyclase deficiency syndrome.

What condition is associated with TKFC p.Arg286Cys (c.856C>T)?

TKFC p.Arg286Cys (c.856C>T) is associated with triokinase and FMN cyclase deficiency syndrome (ClinVar).

How common is TKFC p.Arg286Cys (c.856C>T) in the general population?

TKFC p.Arg286Cys (c.856C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TKFC p.Arg286Cys (c.856C>T)?

AlphaMissense predicts likely benign (score 0.1246) — an in-silico prediction, not a clinical call.

TKFC p.Arg286Cys

c.856C>T · VCV4882717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1246 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

triokinase and FMN cyclase deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.1246	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · 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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00527% 85/1,613,860 alleles · ultra-rare exomes 77/1,461,702 · genomes 8/152,158 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
European (non-Finnish)	0.00559%	17,879
African / African-American	0.00133%	74,908
South Asian	0.0011%	91,090

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.Arg286Cys
Coding: c.856C>T
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61342835 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 286: 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.Arg286His Uncertain significance ★ ⚠ same residue
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

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-arg286cys (accessed [today's date]).

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