Is EBF3 p.Val323Ile (c.967G>A) pathogenic?

EBF3 p.Val323Ile (c.967G>A) is classified Uncertain significance in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). AlphaMissense: likely benign (0.266); Very rare (popmax 0.00446%, eas); Associated with hypotonia, ataxia, and delayed development syndrome.

What condition is associated with EBF3 p.Val323Ile (c.967G>A)?

EBF3 p.Val323Ile (c.967G>A) is associated with hypotonia, ataxia, and delayed development syndrome (ClinVar).

How common is EBF3 p.Val323Ile (c.967G>A) in the general population?

EBF3 p.Val323Ile (c.967G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EBF3 p.Val323Ile (c.967G>A)?

AlphaMissense predicts likely benign (score 0.266) — an in-silico prediction, not a clinical call.

EBF3 p.Val323Ile

c.967G>A · rs375316354 · VCV2688997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypotonia, ataxia, and delayed development syndrome

Computational evidence

Protein change
AlphaMissense	0.266	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 25 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	25.5	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 0.00446% East Asian · 2/44,856 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000929% 15/1,614,104 alleles · very rare exomes 15/1,461,808 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,428
South Asian	0.0022%	45,535
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,510
Finnishnot grpmax-eligible	0.00156%	64,006
European (non-Finnish)	0.000678%	147,502

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.Val323Ile
Coding: c.967G>A
MANE Select: NM_001375380
dbSNP: rs375316354
Type: single nucleotide variant
Location: chr10:129867213 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.89 · 2 PDB
Residue 323: the ipt/tig domain; a β-strand

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 p.Val323Leu Uncertain significance ★ ⚠ same residue
EBF3 p.Val323= Likely benign ★ same residue
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

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-val323ile (accessed [today's date]).

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