Is CUX1 p.Ala5Val (c.14C>T) pathogenic?

CUX1 p.Ala5Val (c.14C>T) is classified Uncertain significance in CUX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-05). AlphaMissense: ambiguous (0.4083); Very rare (popmax 0.00131%, nfe).

How common is CUX1 p.Ala5Val (c.14C>T) in the general population?

CUX1 p.Ala5Val (c.14C>T) is very rare (popmax 0.00131%, nfe) (gnomAD).

What do computational predictors say about CUX1 p.Ala5Val (c.14C>T)?

AlphaMissense predicts ambiguous (score 0.4083) — an in-silico prediction, not a clinical call.

CUX1 p.Ala5Val

c.14C>T · VCV4897214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00131%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4083	ambiguous
REVEL	0.133	moderately benign-leaning
SaProt	LLR -5.90	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.077, phastCons 0.99
Regional constraint	o/e 0.58	unconstrained · MANE · 253 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	19.87	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 0.00131% European (non-Finnish) · 15/1,147,784 alleles

Filtering AF 0.000785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000622%

Overall 0.00107% 15/1,399,930 alleles · very rare

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.Ala5Val
Coding: c.14C>T
MANE Select: NM_181552
Type: single nucleotide variant
Location: chr7:101817653 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.84 · 3 PDB

Full CUX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUX1 p.Ala5= Likely benign ★ same residue
CUX1 c.1451-2A>G Likely pathogenic ★★ same type
CUX1 c.1681-1G>A Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Arg661Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Gln862Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Glu866Ter Pathogenic/Likely pathogenic ★★ same type
CUX1 p.Trp1188Ter Pathogenic ★★ same type
CUX1 p.Ala1433Val 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/cux1-p-ala5val (accessed [today's date]).

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