Is EBF4 p.Ser61Pro (c.181T>C) pathogenic?

EBF4 p.Ser61Pro (c.181T>C) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.4817); Rare (popmax 0.385%, afr).

How common is EBF4 p.Ser61Pro (c.181T>C) in the general population?

EBF4 p.Ser61Pro (c.181T>C) is rare (popmax 0.385%, afr) (gnomAD).

What do computational predictors say about EBF4 p.Ser61Pro (c.181T>C)?

AlphaMissense predicts ambiguous (score 0.4817) — an in-silico prediction, not a clinical call.

EBF4 p.Ser61Pro

c.181T>C · VCV4246258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4817 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.385%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4817	ambiguous
REVEL	0.275	benign-leaning
SaProt	LLR -12.17	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	26.3	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 0.385% African / African-American · 282/73,334 alleles

Filtering AF 0.348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.333%

Overall 0.0202% 314/1,553,330 alleles · rare exomes 122/1,401,110 · genomes 192/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.385%	260
Admixed American	0.0333%	3,004
Remaining individualsnot grpmax-eligible	0.0183%	5,477
South Asian	0.00119%	84,122
European (non-Finnish)	0.000261%	382,573

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.Ser61Pro
Coding: c.181T>C
MANE Select: NM_001395167
Type: single nucleotide variant
Location: chr20:2705620 (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-ser61pro (accessed [today's date]).

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