Is TKFC p.Pro424His (c.1271C>A) pathogenic?

TKFC p.Pro424His (c.1271C>A) is classified Uncertain significance in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.218); No allele count reported in gnomAD v4.1 (AN 1,594,294).

How common is TKFC p.Pro424His (c.1271C>A) in the general population?

TKFC p.Pro424His (c.1271C>A) is no allele count reported in gnomAD v4.1 (AN 1,594,294) (gnomAD).

What do computational predictors say about TKFC p.Pro424His (c.1271C>A)?

AlphaMissense predicts likely benign (score 0.218) — an in-silico prediction, not a clinical call.

TKFC p.Pro424His

c.1271C>A · VCV3456749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.218 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,594,294)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.218	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -13.02	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 1.1	GERP 0.11, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	15.48	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

No allele count reported in gnomAD v4.1 (AN 1,594,294). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TKFC
Protein: p.Pro424His
Coding: c.1271C>A
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61345290 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 424: the dhal 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-pro424his (accessed [today's date]).

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