Is TKFC p.Asp243Asn (c.727G>A) pathogenic?

TKFC p.Asp243Asn (c.727G>A) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.1581); Very rare (popmax 0.00333%, amr).

How common is TKFC p.Asp243Asn (c.727G>A) in the general population?

TKFC p.Asp243Asn (c.727G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TKFC p.Asp243Asn (c.727G>A)?

AlphaMissense predicts likely benign (score 0.1581) — an in-silico prediction, not a clinical call.

TKFC p.Asp243Asn

c.727G>A · rs758305865 · VCV3177695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1581	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -10.06	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 5.1	GERP 0.13, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	19.44	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 0.00333% Admixed American · 2/60,026 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000929% 15/1,613,952 alleles · very rare exomes 15/1,461,652 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,013
South Asian	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000847%	118,002

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.Asp243Asn
Coding: c.727G>A
MANE Select: NM_015533
dbSNP: rs758305865
Type: single nucleotide variant
Location: chr11:61342610 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 243: 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-asp243asn (accessed [today's date]).

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