Is TKFC p.Arg152Trp (c.454C>T) pathogenic?

TKFC p.Arg152Trp (c.454C>T) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.8999); Very rare (popmax 0.004%, afr).

How common is TKFC p.Arg152Trp (c.454C>T) in the general population?

TKFC p.Arg152Trp (c.454C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about TKFC p.Arg152Trp (c.454C>T)?

AlphaMissense predicts likely pathogenic (score 0.8999) — an in-silico prediction, not a clinical call.

TKFC p.Arg152Trp

c.454C>T · VCV3456747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8999	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -15.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,914 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00062% 10/1,612,716 alleles · very rare exomes 8/1,460,532 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,971
Admixed American	0.00333%	29,987
East Asian	0.00223%	44,890
Finnishnot grpmax-eligible	0.00158%	63,120
South Asian	0.0011%	91,042
European (non-Finnish)	0.00017%	589,883

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.Arg152Trp
Coding: c.454C>T
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61339403 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 152: the dhak domain

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

Similar variants

TKFC p.Arg152Gln Uncertain significance ★ ⚠ same residue
TKFC p.Arg152Pro 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

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-arg152trp (accessed [today's date]).

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