Is EBF4 p.Pro100Ala (c.298C>G) pathogenic?

EBF4 p.Pro100Ala (c.298C>G) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0542); Very rare (popmax 0.00958%, afr).

How common is EBF4 p.Pro100Ala (c.298C>G) in the general population?

EBF4 p.Pro100Ala (c.298C>G) is very rare (popmax 0.00958%, afr) (gnomAD).

What do computational predictors say about EBF4 p.Pro100Ala (c.298C>G)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

EBF4 p.Pro100Ala

c.298C>G · VCV4662855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00958%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	19.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00958% African / African-American · 7/73,032 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.00058% 9/1,551,216 alleles · very rare exomes 4/1,399,070 · genomes 5/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00958%	10,433
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,624
Remaining individualsnot grpmax-eligible	0.00166%	60,072

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: EBF4
Protein: p.Pro100Ala
Coding: c.298C>G
MANE Select: NM_001395167
Type: single nucleotide variant
Location: chr20:2705977 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.60

Full EBF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBF4 p.Arg164= Benign ★★ same type
EBF4 p.Ile91= Benign ★★ same type
EBF4 p.Ala102Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala102Val Uncertain significance ★ ⚠ same type
EBF4 p.Ala402Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala40Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala438Ser Uncertain significance ★ ⚠ same type
EBF4 p.Ala522Val Uncertain significance ★ ⚠ 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/ebf4-p-pro100ala (accessed [today's date]).

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