Is EBF3 p.Leu49Pro (c.146T>C) pathogenic?

EBF3 p.Leu49Pro (c.146T>C) is classified Likely benign in EBF3 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9963); Very rare (popmax 0.000782%, nfe); Associated with autism spectrum disorder.

What condition is associated with EBF3 p.Leu49Pro (c.146T>C)?

EBF3 p.Leu49Pro (c.146T>C) is associated with autism spectrum disorder (ClinVar).

How common is EBF3 p.Leu49Pro (c.146T>C) in the general population?

EBF3 p.Leu49Pro (c.146T>C) is very rare (popmax 0.000782%, nfe) (gnomAD).

What do computational predictors say about EBF3 p.Leu49Pro (c.146T>C)?

AlphaMissense predicts likely pathogenic (score 0.9963) — an in-silico prediction, not a clinical call.

EBF3 p.Leu49Pro

c.146T>C · rs777927734 · VCV2429838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000782%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autism spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.9963	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -10.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 4,677 bp · p 1e-06 · regional, not allelic
Overall
CADD	32.0	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 0.000782% European (non-Finnish) · 9/1,150,382 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000579% 9/1,554,744 alleles · very rare exomes 7/1,403,232 · genomes 2/151,512 · joint denominator

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.Leu49Pro
Coding: c.146T>C
MANE Select: NM_001375380
dbSNP: rs777927734
Type: single nucleotide variant
Location: chr10:129963512 (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

Disease context

autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EBF3 p.Gln78Ter Pathogenic ★ same condition
EBF3 p.Ser532fs Uncertain significance ★ same condition
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

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-leu49pro (accessed [today's date]).

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