Is TKFC p.Arg228Gln (c.683G>A) pathogenic?

TKFC p.Arg228Gln (c.683G>A) is classified Uncertain significance in TKFC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.1816); Ultra-rare (popmax 0.0818%, nfe); Associated with triokinase and FMN cyclase deficiency syndrome.

What condition is associated with TKFC p.Arg228Gln (c.683G>A)?

TKFC p.Arg228Gln (c.683G>A) is associated with triokinase and FMN cyclase deficiency syndrome (ClinVar).

How common is TKFC p.Arg228Gln (c.683G>A) in the general population?

TKFC p.Arg228Gln (c.683G>A) is ultra-rare (popmax 0.0818%, nfe) (gnomAD).

What do computational predictors say about TKFC p.Arg228Gln (c.683G>A)?

AlphaMissense predicts likely benign (score 0.1816) — an in-silico prediction, not a clinical call.

TKFC p.Arg228Gln

c.683G>A · VCV3326242

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0818%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

triokinase and FMN cyclase deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.1816	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -10.82	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	32.0	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 0.0818% European (non-Finnish) · 965/1,180,030 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0757%

Overall 0.0725% 1,171/1,614,068 alleles · ultra-rare exomes 1,102/1,461,756 · genomes 69/152,312 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.167%	597
European (non-Finnish)grpmax	0.0818%	1,223
Remaining individualsnot grpmax-eligible	0.0624%	1,603
South Asian	0.0351%	2,846
African / African-American	0.0253%	3,950
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Admixed American	0.00666%	15,004

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg228Gln
Coding: c.683G>A
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61342488 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 228: 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.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
TKFC p.Gly445Ser Likely pathogenic ★ 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-arg228gln (accessed [today's date]).

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