Is TKFC p.Glu532Lys (c.1594G>A) pathogenic?

TKFC p.Glu532Lys (c.1594G>A) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1142); Ultra-rare (popmax 0.0158%, nfe).

How common is TKFC p.Glu532Lys (c.1594G>A) in the general population?

TKFC p.Glu532Lys (c.1594G>A) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about TKFC p.Glu532Lys (c.1594G>A)?

AlphaMissense predicts likely benign (score 0.1142) — an in-silico prediction, not a clinical call.

TKFC p.Glu532Lys

c.1594G>A · rs200053750 · VCV2376748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1142	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -11.78	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 4.8	GERP -0.048, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	22.2	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 0.0158% European (non-Finnish) · 187/1,179,988 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0129% 208/1,612,772 alleles · ultra-rare exomes 193/1,460,458 · genomes 15/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0158%	6,310
South Asian	0.0143%	7,006
Admixed American	0.00833%	12,004
African / African-American	0.00267%	37,514
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Glu532Lys
Coding: c.1594G>A
MANE Select: NM_015533
dbSNP: rs200053750
Type: single nucleotide variant
Location: chr11:61346369 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 532: the dhal domain

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

Similar variants

TKFC p.Glu532Gly 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-glu532lys (accessed [today's date]).

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