Is CUX1 p.Val545Ile (c.1633G>A) pathogenic?

CUX1 p.Val545Ile (c.1633G>A) is classified Conflicting classifications of pathogenicity in CUX1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0643); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with CUX1 p.Val545Ile (c.1633G>A)?

CUX1 p.Val545Ile (c.1633G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CUX1 p.Val545Ile (c.1633G>A) in the general population?

CUX1 p.Val545Ile (c.1633G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CUX1 p.Val545Ile (c.1633G>A)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

CUX1 p.Val545Ile

c.1633G>A · rs376833286 · VCV2657863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.1
Regional constraint	o/e 0.90	unconstrained · MANE · 127 kb · p 0.013 · regional, not allelic
Overall
CADD	7.892	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 0.00833% Admixed American · 5/60,012 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000991% 16/1,614,106 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,002
South Asian	0.00329%	30,365
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,030
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000424%	236,010

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: CUX1
Protein: p.Val545Ile
Coding: c.1633G>A
MANE Select: NM_181552
dbSNP: rs376833286
Type: single nucleotide variant
Location: chr7:102197044 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.84 · 3 PDB
Residue 545: a DNA-binding region; the 'disordered' region; a UniProt-annotated variant site (in)

Full CUX1 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

CUX1 p.Ala1433Val Uncertain significance ★★ ⚠ same condition
CUX1 p.Asp1419Gly Uncertain significance ★★ ⚠ same condition
CUX1 p.Asp704Glu Uncertain significance ★★ ⚠ same condition
CUX1 p.Cys802Tyr Uncertain significance ★★ ⚠ same condition
CUX1 p.Gly543Arg Uncertain significance ★★ ⚠ same condition
CUX1 p.His1293Tyr Uncertain significance ★★ ⚠ same condition
CUX1 p.Ile160Thr Uncertain significance ★★ ⚠ same condition
CUX1 p.Pro1367Arg 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/cux1-p-val545ile (accessed [today's date]).

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