Is TKFC p.Val437= (c.1311C>T) pathogenic?

TKFC p.Val437= (c.1311C>T) is classified Benign in TKFC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-27). Common (popmax 99.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with triokinase and FMN cyclase deficiency syndrome.

What condition is associated with TKFC p.Val437= (c.1311C>T)?

TKFC p.Val437= (c.1311C>T) is associated with triokinase and FMN cyclase deficiency syndrome (ClinVar).

TKFC p.Val437=

Q: How common is TKFC p.Val437= (c.1311C>T) in the general population?

TKFC p.Val437= (c.1311C>T) is common (popmax 99.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1311C>T · rs2305465 · VCV1255453

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 99.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

triokinase and FMN cyclase deficiency syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -4.6, phastCons 0.077
Overall
CADD	6.667	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.3% European (non-Finnish) · 1,166,073/1,174,838 alleles

Filtering AF 99.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 99%

Overall 95.7% 1,537,055/1,606,252 alleles · common exomes 1,409,241/1,454,000 · genomes 127,814/152,252 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
European (non-Finnish)grpmax	99.3%	1
Ashkenazi Jewishnot grpmax-eligible	98.8%	1
Finnishnot grpmax-eligible	98.6%	1
East Asian	96.6%	1
Admixed American	96.2%	1
Middle Eastern	94.2%	1
Remaining individualsnot grpmax-eligible	94%	1
South Asian	87.3%	1
African / African-American	46.8%	2

Amish 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.Val437=
Coding: c.1311C>T
MANE Select: NM_015533
dbSNP: rs2305465
Type: single nucleotide variant
Location: chr11:61345330 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 437: the dhal 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.Val437Phe 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-val437 (accessed [today's date]).

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