Is TKFC p.Leu516Arg (c.1547T>G) pathogenic?

TKFC p.Leu516Arg (c.1547T>G) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1281); Very rare (popmax 0.00932%, nfe).

How common is TKFC p.Leu516Arg (c.1547T>G) in the general population?

TKFC p.Leu516Arg (c.1547T>G) is very rare (popmax 0.00932%, nfe) (gnomAD).

What do computational predictors say about TKFC p.Leu516Arg (c.1547T>G)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

TKFC p.Leu516Arg

c.1547T>G · rs202013095 · VCV2304637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -8.25	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 6.1	GERP 2.3, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	18.93	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 0.00932% European (non-Finnish) · 110/1,180,018 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00712% 115/1,614,038 alleles · very rare exomes 110/1,461,746 · genomes 5/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00932%	10,727
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.00133%	75,048

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.Leu516Arg
Coding: c.1547T>G
MANE Select: NM_015533
dbSNP: rs202013095
Type: single nucleotide variant
Location: chr11:61345918 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 516: the dhal domain

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

Similar variants

TKFC p.Leu516Val Uncertain significance ★ ⚠ same residue
TKFC p.Arg543Ile Likely pathogenic ★★ same type
TKFC p.Arg228Gln Uncertain significance ★★ ⚠ same type
TKFC p.Asp403Asn Uncertain significance ★★ ⚠ same type
TKFC p.Gln257Pro Uncertain significance ★★ ⚠ same type
TKFC c.194-13C>T Benign ★★ same type
TKFC c.775+39A>C Benign ★★ same type
TKFC p.Ala185Thr Benign ★★ same type

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-leu516arg (accessed [today's date]).

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