Is EBF3 p.Val446Ile (c.1336G>A) pathogenic?

EBF3 p.Val446Ile (c.1336G>A) is classified Likely benign in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: likely benign (0.1167); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with EBF3 p.Val446Ile (c.1336G>A)?

EBF3 p.Val446Ile (c.1336G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EBF3 p.Val446Ile (c.1336G>A) in the general population?

EBF3 p.Val446Ile (c.1336G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about EBF3 p.Val446Ile (c.1336G>A)?

AlphaMissense predicts likely benign (score 0.1167) — an in-silico prediction, not a clinical call.

EBF3 p.Val446Ile

c.1336G>A · VCV4015925

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1167	likely benign
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -7.34	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 10 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	25.7	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 0.0134% East Asian · 6/44,884 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00204% 33/1,614,136 alleles · ultra-rare exomes 29/1,461,886 · genomes 4/152,250 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
East Asiangrpmax	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Admixed American	0.00333%	30,005
African / African-American	0.00133%	74,948
South Asian	0.0011%	91,094
European (non-Finnish)	0.000678%	147,507

Ashkenazi Jewish 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: EBF3
Protein: p.Val446Ile
Coding: c.1336G>A
MANE Select: NM_001375380
Type: single nucleotide variant
Location: chr10:129842152 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EBF3 p.Arg152Gly Pathogenic ★★ same condition
EBF3 p.Arg163Gln Pathogenic ★★ same condition
EBF3 p.Arg209Gln Pathogenic/Likely pathogenic ★★ same condition
EBF3 c.*9A>G Uncertain significance ★★ ⚠ same condition
EBF3 p.Asn100Asp Uncertain significance ★★ ⚠ same condition
EBF3 p.Asp286Asn Uncertain significance ★★ ⚠ same condition
EBF3 p.Gly291Arg Uncertain significance ★★ ⚠ same condition
EBF3 p.Thr33Ala Benign/Likely benign ★★ 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-val446ile (accessed [today's date]).

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