Is TKFC p.Asp403Asn (c.1207G>A) pathogenic?

TKFC p.Asp403Asn (c.1207G>A) is classified Uncertain significance in TKFC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.8684); Ultra-rare (popmax 0.0185%, mid); Associated with triokinase and FMN cyclase deficiency syndrome.

What condition is associated with TKFC p.Asp403Asn (c.1207G>A)?

TKFC p.Asp403Asn (c.1207G>A) is associated with triokinase and FMN cyclase deficiency syndrome (ClinVar).

How common is TKFC p.Asp403Asn (c.1207G>A) in the general population?

TKFC p.Asp403Asn (c.1207G>A) is ultra-rare (popmax 0.0185%, mid) (gnomAD).

What do computational predictors say about TKFC p.Asp403Asn (c.1207G>A)?

AlphaMissense predicts likely pathogenic (score 0.8684) — an in-silico prediction, not a clinical call.

TKFC p.Asp403Asn

c.1207G>A · rs754625426 · VCV2371668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

triokinase and FMN cyclase deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.8684	likely pathogenic
REVEL	0.625	indeterminate
SaProt	LLR -14.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	30.0	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 0.0185% Middle Eastern · 1/5,416 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00242% 39/1,612,726 alleles · ultra-rare exomes 37/1,460,554 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0185%	5,416
European (non-Finnish)	0.00288%	34,707
East Asian	0.00223%	44,886
Finnishnot grpmax-eligible	0.00157%	63,584
African / African-American	0.00134%	74,872
South Asian	0.0011%	91,034

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.Asp403Asn
Coding: c.1207G>A
MANE Select: NM_015533
dbSNP: rs754625426
Type: single nucleotide variant
Location: chr11:61344240 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 403: the dhal domain; a binding site

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 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-asp403asn (accessed [today's date]).

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