Is EBF4 p.Leu503Pro (c.1508T>C) pathogenic?

EBF4 p.Leu503Pro (c.1508T>C) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-27). AlphaMissense: ambiguous (0.4507); Very rare (popmax 0.000602%, nfe).

How common is EBF4 p.Leu503Pro (c.1508T>C) in the general population?

EBF4 p.Leu503Pro (c.1508T>C) is very rare (popmax 0.000602%, nfe) (gnomAD).

What do computational predictors say about EBF4 p.Leu503Pro (c.1508T>C)?

AlphaMissense predicts ambiguous (score 0.4507) — an in-silico prediction, not a clinical call.

EBF4 p.Leu503Pro

c.1508T>C · rs974575764 · VCV2339598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000602%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4507	ambiguous
REVEL	0.294	indeterminate
SaProt	LLR -7.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 9,329 bp · p 0.2 · regional, not allelic
Overall
CADD	32.0	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 0.000602% European (non-Finnish) · 6/996,594 alleles

Filtering AF 0.000217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000142%

Overall 0.000479% 6/1,253,366 alleles · very rare exomes 6/1,101,256 · genomes 0/152,110 · 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: EBF4
Protein: p.Leu503Pro
Coding: c.1508T>C
MANE Select: NM_001395167
dbSNP: rs974575764
Type: single nucleotide variant
Location: chr20:2752513 (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-leu503pro (accessed [today's date]).

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