Is TKFC p.Arg297His (c.890G>A) pathogenic?

TKFC p.Arg297His (c.890G>A) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: ambiguous (0.4315); Very rare (popmax 0.00891%, eas).

How common is TKFC p.Arg297His (c.890G>A) in the general population?

TKFC p.Arg297His (c.890G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about TKFC p.Arg297His (c.890G>A)?

AlphaMissense predicts ambiguous (score 0.4315) — an in-silico prediction, not a clinical call.

TKFC p.Arg297His

c.890G>A · rs376236721 · VCV2216488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Computational evidence

Protein change
AlphaMissense	0.4315	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -13.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	32.0	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 0.00891% East Asian · 4/44,882 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00204% 33/1,614,172 alleles · very rare exomes 28/1,461,854 · genomes 5/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
African / African-American	0.008%	12,507
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.00153%	65,557
South Asian	0.0011%	91,084

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.Arg297His
Coding: c.890G>A
MANE Select: NM_015533
dbSNP: rs376236721
Type: single nucleotide variant
Location: chr11:61343366 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 297: the dhak domain

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

Similar variants

TKFC p.Arg297Cys Uncertain significance ★ ⚠ same residue
TKFC p.Arg297Leu 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-arg297his (accessed [today's date]).

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