Is CBFA2T2 p.Val451Ile (c.1351G>A) pathogenic?

CBFA2T2 p.Val451Ile (c.1351G>A) is classified Uncertain significance in CBFA2T2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-23). AlphaMissense: ambiguous (0.4486); Very rare (popmax 0.00178%, nfe).

How common is CBFA2T2 p.Val451Ile (c.1351G>A) in the general population?

CBFA2T2 p.Val451Ile (c.1351G>A) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about CBFA2T2 p.Val451Ile (c.1351G>A)?

AlphaMissense predicts ambiguous (score 0.4486) — an in-silico prediction, not a clinical call.

CBFA2T2 p.Val451Ile

c.1351G>A · VCV3485558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4486	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -8.02	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 12	GERP 6.6, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 4,096 bp · p 3.2e-09 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V460I vs ClinVar V451I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,054 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00097%

Overall 0.00155% 25/1,614,128 alleles · very rare exomes 21/1,461,872 · genomes 4/152,256 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.00178%	56,193
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,948

Remaining individuals 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: CBFA2T2
Protein: p.Val451Ile
Coding: c.1351G>A
MANE Select: NM_001032999
Type: single nucleotide variant
Location: chr20:33640394 (GRCh38)
Gene constraint: LOEUF 0.314 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.92
Residue 460 UniProt numbering: the 'nervy homology region 3 (nhr3)' region

Full CBFA2T2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBFA2T2 c.35-32725G>A Uncertain significance ★ ⚠ same type
CBFA2T2 c.35-32739G>T Uncertain significance ★ ⚠ same type
CBFA2T2 c.35-32746G>A Uncertain significance ★ ⚠ same type
CBFA2T2 c.35-32749A>G Uncertain significance ★ ⚠ same type
CBFA2T2 c.35-32751C>T Uncertain significance ★ ⚠ same type
CBFA2T2 p.Ala184Thr Uncertain significance ★ ⚠ same type
CBFA2T2 p.Ala186Val Uncertain significance ★ ⚠ same type
CBFA2T2 p.Ala345Val 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/cbfa2t2-p-val451ile (accessed [today's date]).

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