Is CUX2 p.Arg34Trp (c.100C>T) pathogenic?

CUX2 p.Arg34Trp (c.100C>T) is classified Conflicting classifications of pathogenicity in CUX2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-06). AlphaMissense: likely pathogenic (0.6979); Ultra-rare (popmax 0.0497%, mid).

How common is CUX2 p.Arg34Trp (c.100C>T) in the general population?

CUX2 p.Arg34Trp (c.100C>T) is ultra-rare (popmax 0.0497%, mid) (gnomAD).

What do computational predictors say about CUX2 p.Arg34Trp (c.100C>T)?

AlphaMissense predicts likely pathogenic (score 0.6979) — an in-silico prediction, not a clinical call.

CUX2 p.Arg34Trp

c.100C>T · VCV3337981

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0497%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6979	likely pathogenic
REVEL	0.125	moderately benign-leaning
SaProt	LLR -13.83	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 180 kb · p 0.91 · regional, not allelic
Overall
CADD	28.6	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 0.0497% Middle Eastern · 3/6,036 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0304% 488/1,603,310 alleles · ultra-rare exomes 462/1,454,062 · genomes 26/149,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0497%	2,012
European (non-Finnish)	0.0366%	2,735
Remaining individualsnot grpmax-eligible	0.029%	3,452
Finnishnot grpmax-eligible	0.0254%	3,940
East Asian	0.0248%	4,027
Admixed American	0.00512%	19,532
African / African-American	0.0041%	24,397
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,444
South Asian	0.00335%	29,814

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.Arg34Trp
Coding: c.100C>T
MANE Select: NM_015267
Type: single nucleotide variant
Location: chr12:111214236 (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

Similar variants

CUX2 p.Glu590Lys Pathogenic/Likely pathogenic ★★ same type
CUX2 p.Ala302Ser Uncertain significance ★★ ⚠ same type
CUX2 p.Ala336Thr Uncertain significance ★★ ⚠ same type
CUX2 p.Ala544Val Uncertain significance ★★ ⚠ same type
CUX2 p.Arg312Gln Uncertain significance ★★ ⚠ same type
CUX2 p.Arg599Ser Uncertain significance ★★ ⚠ same type
CUX2 p.Arg701His Uncertain significance ★★ same type
CUX2 p.Arg903His Uncertain significance ★★ ⚠ 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/cux2-p-arg34trp (accessed [today's date]).

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