Is TKFC p.Ile67Thr (c.200T>C) pathogenic?

TKFC p.Ile67Thr (c.200T>C) is classified Likely benign in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely benign (0.2564); Low-frequency (popmax 1.16%, eas).

How common is TKFC p.Ile67Thr (c.200T>C) in the general population?

TKFC p.Ile67Thr (c.200T>C) is low-frequency (popmax 1.16%, eas) (gnomAD).

What do computational predictors say about TKFC p.Ile67Thr (c.200T>C)?

AlphaMissense predicts likely benign (score 0.2564) — an in-silico prediction, not a clinical call.

TKFC p.Ile67Thr

c.200T>C · VCV3388029

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2564 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.16%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2564	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	25.6	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 1.16% East Asian · 520/44,858 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.0537% 866/1,612,392 alleles · low-frequency exomes 761/1,460,092 · genomes 105/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.16%	86
South Asian	0.195%	514
Remaining individualsnot grpmax-eligible	0.13%	771
Middle Eastern	0.0351%	2,853
Admixed American	0.0117%	8,564
European (non-Finnish)	0.00636%	15,723
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
African / African-American	0.00267%	37,506
Finnishnot grpmax-eligible	0.00157%	63,802

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.Ile67Thr
Coding: c.200T>C
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61339072 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 67: the dhak domain

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

Similar variants

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
TKFC p.Thr157= 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-ile67thr (accessed [today's date]).

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