Is EBF3 p.Pro99Leu (c.296C>T) pathogenic?

EBF3 p.Pro99Leu (c.296C>T) is classified Uncertain significance in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely benign (0.0818); Very rare (popmax 0.00167%, amr).

How common is EBF3 p.Pro99Leu (c.296C>T) in the general population?

EBF3 p.Pro99Leu (c.296C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EBF3 p.Pro99Leu (c.296C>T)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

EBF3 p.Pro99Leu

c.296C>T · VCV3899804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -4.18	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 9.9	GERP -0.12, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 4,677 bp · p 1e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,986 alleles · very rare exomes 3/1,461,812 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
South Asian	0.0011%	91,080
European (non-Finnish)	0.000169%	590,002

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: EBF3
Protein: p.Pro99Leu
Coding: c.296C>T
MANE Select: NM_001375380
Type: single nucleotide variant
Location: chr10:129963001 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.89 · 2 PDB

Full EBF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBF3 c.486-1G>A Pathogenic ★★ same type
EBF3 c.555-2A>G Likely pathogenic ★★ same type
EBF3 p.Arg152Gly Pathogenic ★★ same type
EBF3 p.Arg163Gln Pathogenic ★★ same type
EBF3 p.Arg163Leu Pathogenic ★★ same type
EBF3 p.Arg163Trp Pathogenic/Likely pathogenic ★★ same type
EBF3 p.Arg206Ter Pathogenic ★★ same type
EBF3 p.Arg209Gln Pathogenic/Likely pathogenic ★★ 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/ebf3-p-pro99leu (accessed [today's date]).

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