Is CUX2 p.Pro144Ser (c.430C>T) pathogenic?

CUX2 p.Pro144Ser (c.430C>T) is classified Likely benign in CUX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0355%, nfe).

How common is CUX2 p.Pro144Ser (c.430C>T) in the general population?

CUX2 p.Pro144Ser (c.430C>T) is ultra-rare (popmax 0.0355%, nfe) (gnomAD).

What do computational predictors say about CUX2 p.Pro144Ser (c.430C>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

CUX2 p.Pro144Ser

c.430C>T · rs200363695 · VCV2570845

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0355%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.95	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 1.5	GERP 0.18, phastCons 0.76
Regional constraint	o/e 0.74	unconstrained · MANE · 93 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	14.01	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 0.0355% European (non-Finnish) · 418/1,176,832 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0316%

Overall 0.0734% 1,179/1,607,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.19%	46
Remaining individualsnot grpmax-eligible	0.145%	692
European (non-Finnish)grpmax	0.0355%	2,815
Admixed American	0.0322%	3,103
Middle Eastern	0.0165%	6,052
African / African-American	0.00669%	14,943
Finnishnot grpmax-eligible	0.00313%	31,993

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro144Ser
Coding: c.430C>T
MANE Select: NM_015267
dbSNP: rs200363695
Type: single nucleotide variant
Location: chr12:111291546 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.99 · 3 PDB
Residue 144: the 'disordered' region

Full CUX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUX2 p.Pro144Leu Uncertain significance ★ ⚠ same residue
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

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-pro144ser (accessed [today's date]).

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