Is CHUK p.Arg424His (c.1271G>A) pathogenic?

CHUK p.Arg424His (c.1271G>A) is classified Uncertain significance in CHUK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). AlphaMissense: ambiguous (0.4927); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CHUK p.Arg424His (c.1271G>A)?

CHUK p.Arg424His (c.1271G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CHUK p.Arg424His (c.1271G>A) in the general population?

CHUK p.Arg424His (c.1271G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHUK p.Arg424His (c.1271G>A)?

AlphaMissense predicts ambiguous (score 0.4927) — an in-silico prediction, not a clinical call.

CHUK p.Arg424His

c.1271G>A · VCV3833360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4927	ambiguous
REVEL	0.591	indeterminate
SaProt	LLR -10.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 16 kb · p 3.3e-05 · 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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000868% 14/1,613,810 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,900
South Asian	0.0011%	91,078
European (non-Finnish)	0.000848%	117,988

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.Arg424His
Coding: c.1271G>A
MANE Select: NM_001278
Type: single nucleotide variant
Location: chr10:100205160 (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.Arg424Cys 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-arg424his (accessed [today's date]).

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