Is TKFC p.Arg567Trp (c.1699C>T) pathogenic?

TKFC p.Arg567Trp (c.1699C>T) is classified Likely benign in TKFC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-28). AlphaMissense: likely benign (0.2677); Rare (popmax 0.362%, amr); Associated with TKFC-related disorder.

What condition is associated with TKFC p.Arg567Trp (c.1699C>T)?

TKFC p.Arg567Trp (c.1699C>T) is associated with TKFC-related disorder (ClinVar).

How common is TKFC p.Arg567Trp (c.1699C>T) in the general population?

TKFC p.Arg567Trp (c.1699C>T) is rare (popmax 0.362%, amr) (gnomAD).

What do computational predictors say about TKFC p.Arg567Trp (c.1699C>T)?

AlphaMissense predicts likely benign (score 0.2677) — an in-silico prediction, not a clinical call.

TKFC p.Arg567Trp

c.1699C>T · rs139056511 · VCV3048735

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2677 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.362%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TKFC-related disorder

Computational evidence

Protein change
AlphaMissense	0.2677	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -13.12	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 3.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	24.9	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 0.362% Admixed American · 217/59,980 alleles

Filtering AF 0.322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.307%

Overall 0.0742% 1,194/1,608,942 alleles · rare exomes 1,036/1,456,604 · genomes 158/152,338 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.362%	276
Middle Eastern	0.348%	288
Remaining individualsnot grpmax-eligible	0.191%	525
African / African-American	0.0666%	1,501
European (non-Finnish)	0.0644%	1,553
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
South Asian	0.00879%	11,377
East Asian	0.00223%	44,832

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.Arg567Trp
Coding: c.1699C>T
MANE Select: NM_015533
dbSNP: rs139056511
Type: single nucleotide variant
Location: chr11:61346474 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 567: the dhal domain

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

Disease context

TKFC-related disorder

Similar variants

TKFC p.Gly445Ser Likely pathogenic ★ same condition
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-arg567trp (accessed [today's date]).

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