Is CHUK p.Arg424Cys (c.1270C>T) pathogenic?

CHUK p.Arg424Cys (c.1270C>T) is classified Uncertain significance in CHUK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-04). AlphaMissense: likely pathogenic (0.5663); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with CHUK p.Arg424Cys (c.1270C>T)?

CHUK p.Arg424Cys (c.1270C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHUK p.Arg424Cys (c.1270C>T) in the general population?

CHUK p.Arg424Cys (c.1270C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CHUK p.Arg424Cys (c.1270C>T)?

AlphaMissense predicts likely pathogenic (score 0.5663) — an in-silico prediction, not a clinical call.

CHUK p.Arg424Cys

c.1270C>T · rs483352712 · VCV2263010

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5663	likely pathogenic
REVEL	0.705	pathogenic-leaning
SaProt	LLR -11.08	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 12	GERP -0.034, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 16 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.0013% 21/1,613,712 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.00127%	78,652
South Asian	0.0011%	91,074

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: CHUK
Protein: p.Arg424Cys
Coding: c.1270C>T
MANE Select: NM_001278
dbSNP: rs483352712
Type: single nucleotide variant
Location: chr10:100205161 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.39 (gnomAD)
Structure: AlphaFold pLDDT 84.41 · 5 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHUK p.Arg424His Uncertain significance ★ same residue
CHUK p.Arg424Gly Uncertain significance ⚠ same residue
CHUK p.Arg365Gln Uncertain significance ★★ ⚠ same condition
CHUK p.Arg563Cys Uncertain significance ★★ ⚠ same condition
CHUK p.Arg563His Uncertain significance ★★ ⚠ same condition
CHUK p.Gln226Pro Uncertain significance ★★ ⚠ same condition
CHUK p.His520Arg Uncertain significance ★★ ⚠ same condition
CHUK p.Lys512Arg Uncertain significance ★★ ⚠ same condition

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/chuk-p-arg424cys (accessed [today's date]).

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