Is EBF3 p.Val181Ile (c.541G>A) pathogenic?

EBF3 p.Val181Ile (c.541G>A) is classified Uncertain significance in EBF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.398); Very rare (popmax 0.000255%, nfe).

How common is EBF3 p.Val181Ile (c.541G>A) in the general population?

EBF3 p.Val181Ile (c.541G>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about EBF3 p.Val181Ile (c.541G>A)?

AlphaMissense predicts ambiguous (score 0.398) — an in-silico prediction, not a clinical call.

EBF3 p.Val181Ile

c.541G>A · VCV4755863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Computational evidence

Protein change
AlphaMissense	0.398	ambiguous
REVEL	0.292	indeterminate
SaProt	LLR -9.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 85 kb · p 4.3e-15 · regional, not allelic
Overall
CADD	25.2	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 0.000255% European (non-Finnish) · 3/1,176,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000187% 3/1,608,074 alleles · very rare exomes 3/1,455,748 · genomes 0/152,326 · 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.Val181Ile
Coding: c.541G>A
MANE Select: NM_001375380
Type: single nucleotide variant
Location: chr10:129957271 (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-val181ile (accessed [today's date]).

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