Is EBF4 p.Arg553Lys (c.1658G>A) pathogenic?

EBF4 p.Arg553Lys (c.1658G>A) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely benign (0.1255); Rare (popmax 0.365%, nfe).

How common is EBF4 p.Arg553Lys (c.1658G>A) in the general population?

EBF4 p.Arg553Lys (c.1658G>A) is rare (popmax 0.365%, nfe) (gnomAD).

What do computational predictors say about EBF4 p.Arg553Lys (c.1658G>A)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

EBF4 p.Arg553Lys

c.1658G>A · rs143929858 · VCV2212133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.365%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -5.46	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 9.6	GERP -2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 9,329 bp · p 0.2 · regional, not allelic
Overall
CADD	22.6	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 0.365% European (non-Finnish) · 4,191/1,146,932 alleles

Filtering AF 0.356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.352%

Overall 0.29% 4,496/1,551,024 alleles · rare exomes 4,206/1,398,784 · genomes 290/152,240 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.365%	274
Remaining individualsnot grpmax-eligible	0.276%	362
Admixed American	0.173%	580
African / African-American	0.0561%	1,784
Middle Eastern	0.0501%	1,997
Finnishnot grpmax-eligible	0.00843%	11,867
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,646
South Asian	0.00119%	84,062

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.Arg553Lys
Coding: c.1658G>A
MANE Select: NM_001395167
dbSNP: rs143929858
Type: single nucleotide variant
Location: chr20:2755744 (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-arg553lys (accessed [today's date]).

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