Is CUX2 p.Arg701His (c.2102G>A) pathogenic?

CUX2 p.Arg701His (c.2102G>A) is classified Uncertain significance in CUX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: ambiguous (0.5593); Ultra-rare (popmax 0.0136%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUX2 p.Arg701His (c.2102G>A)?

CUX2 p.Arg701His (c.2102G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CUX2 p.Arg701His (c.2102G>A) in the general population?

CUX2 p.Arg701His (c.2102G>A) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about CUX2 p.Arg701His (c.2102G>A)?

AlphaMissense predicts ambiguous (score 0.5593) — an in-silico prediction, not a clinical call.

CUX2 p.Arg701His

c.2102G>A · rs944926366 · VCV2598450

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5593 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5593	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -10.89	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 8,582 bp · p 0.88 · regional, not allelic
Overall
CADD	27.9	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 0.0136% Admixed American · 7/51,480 alleles

Filtering AF 0.00633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00452%

Overall 0.000899% 14/1,557,354 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,354
Finnishnot grpmax-eligible	0.00188%	53,248
South Asian	0.00117%	85,194
European (non-Finnish)	0.000433%	230,995

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: CUX2
Protein: p.Arg701His
Coding: c.2102G>A
MANE Select: NM_015267
dbSNP: rs944926366
Type: single nucleotide variant
Location: chr12:111320111 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB

Full CUX2 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

CUX2 p.Arg701Cys Uncertain significance ★ same residue
CUX2 p.Arg701Ser Uncertain significance ★ ⚠ same residue
CUX2 p.Ala302Ser Uncertain significance ★★ ⚠ same condition
CUX2 p.Ala336Thr Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
CUX2 p.Arg954Cys Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp1334Asn Uncertain significance ★★ ⚠ same condition
CUX2 p.Asp844Gly 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/cux2-p-arg701his (accessed [today's date]).

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