Is EBF2 p.His223Tyr (c.667C>T) pathogenic?

EBF2 p.His223Tyr (c.667C>T) is classified Uncertain significance in EBF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.3282); Very rare (popmax 0.00017%, nfe).

How common is EBF2 p.His223Tyr (c.667C>T) in the general population?

EBF2 p.His223Tyr (c.667C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about EBF2 p.His223Tyr (c.667C>T)?

AlphaMissense predicts likely benign (score 0.3282) — an in-silico prediction, not a clinical call.

EBF2 p.His223Tyr

c.667C>T · VCV4246236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3282	likely benign
REVEL	0.498	indeterminate
SaProt	LLR -10.23	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 178 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	26.5	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 0.00017% European (non-Finnish) · 2/1,179,924 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)grpmax	0.00017%	589,964

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EBF2
Protein: p.His223Tyr
Coding: c.667C>T
MANE Select: NM_022659
Type: single nucleotide variant
Location: chr8:25889836 (GRCh38)
Gene constraint: LOEUF 0.394 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.38

Full EBF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBF2 c.1164+4A>G Benign ★★ same type
EBF2 p.Lys352= Benign ★★ same type
EBF2 p.Ala420Thr Uncertain significance ★ ⚠ same type
EBF2 p.Ala47Gly Uncertain significance ★ ⚠ same type
EBF2 p.Ala47Ser Uncertain significance ★ ⚠ same type
EBF2 p.Ala555Thr Uncertain significance ★ ⚠ same type
EBF2 p.Ala87Thr Uncertain significance ★ ⚠ same type
EBF2 p.Arg128Ser 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/ebf2-p-his223tyr (accessed [today's date]).

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