Is EBF4 p.Ser460Cys (c.1379C>G) pathogenic?

EBF4 p.Ser460Cys (c.1379C>G) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.1591); Very rare (popmax 0.00611%, sas).

How common is EBF4 p.Ser460Cys (c.1379C>G) in the general population?

EBF4 p.Ser460Cys (c.1379C>G) is very rare (popmax 0.00611%, sas) (gnomAD).

What do computational predictors say about EBF4 p.Ser460Cys (c.1379C>G)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

EBF4 p.Ser460Cys

c.1379C>G · rs1057403868 · VCV2603168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00611%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -12.42	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 9,329 bp · p 0.2 · regional, not allelic
Overall
CADD	31.0	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 0.00611% South Asian · 2/32,744 alleles

Filtering AF 0.00101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000378%

Overall 0.000481% 6/1,247,062 alleles · very rare exomes 5/1,095,768 · genomes 1/151,294 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00611%	16,372
Remaining individualsnot grpmax-eligible	0.00444%	22,538
European (non-Finnish)	0.000201%	498,296

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.Ser460Cys
Coding: c.1379C>G
MANE Select: NM_001395167
dbSNP: rs1057403868
Type: single nucleotide variant
Location: chr20:2752384 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.60
Residue 460: the 'disordered' region

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-ser460cys (accessed [today's date]).

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