Is CBX4 p.Thr437Ile (c.1310C>T) pathogenic?

CBX4 p.Thr437Ile (c.1310C>T) is classified Uncertain significance in CBX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: ambiguous (0.4167); Rare (popmax 0.15%, afr).

How common is CBX4 p.Thr437Ile (c.1310C>T) in the general population?

CBX4 p.Thr437Ile (c.1310C>T) is rare (popmax 0.15%, afr) (gnomAD).

What do computational predictors say about CBX4 p.Thr437Ile (c.1310C>T)?

AlphaMissense predicts ambiguous (score 0.4167) — an in-silico prediction, not a clinical call.

CBX4 p.Thr437Ile

c.1310C>T · rs375182651 · VCV2459467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4167 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4167	ambiguous
REVEL	0.166	moderately benign-leaning
SaProt	LLR -7.47	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,409 bp · p 0.52 · regional, not allelic
Overall
CADD	24.6	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 0.15% African / African-American · 112/74,494 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.119%

Overall 0.00799% 127/1,589,046 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.15%	665
Admixed American	0.0122%	8,207
Remaining individualsnot grpmax-eligible	0.00976%	10,245
European (non-Finnish)	0.000171%	585,329

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: CBX4
Protein: p.Thr437Ile
Coding: c.1310C>T
MANE Select: NM_003655
dbSNP: rs375182651
Type: single nucleotide variant
Location: chr17:79834332 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 55.01 · 3 PDB
Residue 437: the 'interaction with bmi1' region

Full CBX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX4 p.Arg70= Benign ★★ same type
CBX4 p.Ala138Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala236Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala298Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala314Pro Uncertain significance ★ ⚠ same type
CBX4 p.Ala316Ser Uncertain significance ★ ⚠ same type
CBX4 p.Ala316Thr Uncertain significance ★ ⚠ same type
CBX4 p.Ala323Glu 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/cbx4-p-thr437ile (accessed [today's date]).

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