Is EBF3 p.Arg246His (c.737G>A) pathogenic?

EBF3 p.Arg246His (c.737G>A) is classified Uncertain significance in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-27). AlphaMissense: likely pathogenic (0.9512); Very rare (popmax 0.00672%, afr); Associated with hypotonia, ataxia, and delayed development syndrome.

What condition is associated with EBF3 p.Arg246His (c.737G>A)?

EBF3 p.Arg246His (c.737G>A) is associated with hypotonia, ataxia, and delayed development syndrome (ClinVar).

How common is EBF3 p.Arg246His (c.737G>A) in the general population?

EBF3 p.Arg246His (c.737G>A) is very rare (popmax 0.00672%, afr) (gnomAD).

What do computational predictors say about EBF3 p.Arg246His (c.737G>A)?

AlphaMissense predicts likely pathogenic (score 0.9512) — an in-silico prediction, not a clinical call.

EBF3 p.Arg246His

c.737G>A · rs570873800 · VCV2441166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypotonia, ataxia, and delayed development syndrome

Computational evidence

Protein change
AlphaMissense	0.9512	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -14.28	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 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 25 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00672% African / African-American · 5/74,436 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00207% 33/1,592,354 alleles · very rare exomes 26/1,439,968 · genomes 7/152,386 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00672%	14,887
European (non-Finnish)	0.0024%	41,675

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.Arg246His
Coding: c.737G>A
MANE Select: NM_001375380
dbSNP: rs570873800
Type: single nucleotide variant
Location: chr10:129873496 (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

hypotonia, ataxia, and delayed development syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EBF3 c.486-1G>A Pathogenic ★★ same condition
EBF3 c.555-2A>G Likely pathogenic ★★ same condition
EBF3 p.Arg163Gln Pathogenic ★★ same condition
EBF3 p.Arg163Leu Pathogenic ★★ same condition
EBF3 p.Arg163Trp Pathogenic/Likely pathogenic ★★ same condition
EBF3 p.Arg206Ter Pathogenic ★★ same condition
EBF3 p.Arg209Gln Pathogenic/Likely pathogenic ★★ same condition
EBF3 p.Arg209Trp Pathogenic/Likely pathogenic ★★ same condition

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-arg246his (accessed [today's date]).

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