Is EFNB2 p.Leu221= (c.663C>T) pathogenic?

EFNB2 p.Leu221= (c.663C>T) is classified Likely benign in EFNB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-04). Ultra-rare (popmax 0.0333%, amr); Associated with EFNB2-related disorder.

What condition is associated with EFNB2 p.Leu221= (c.663C>T)?

EFNB2 p.Leu221= (c.663C>T) is associated with EFNB2-related disorder (ClinVar).

How common is EFNB2 p.Leu221= (c.663C>T) in the general population?

EFNB2 p.Leu221= (c.663C>T) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

EFNB2 p.Leu221=

c.663C>T · rs144052492 · VCV3057815

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Conditions

EFNB2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -5.8, phastCons 0.004
Overall
CADD	9.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,012 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00489% 79/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0096%	10,414
East Asian	0.00891%	11,220
African / African-American	0.004%	24,971
European (non-Finnish)	0.0039%	25,652

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: EFNB2
Protein: p.Leu221=
Coding: c.663C>T
MANE Select: NM_004093
dbSNP: rs144052492
Type: single nucleotide variant
Location: chr13:106493379 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.60 · 10 PDB

Full EFNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EFNB2-related disorder

Similar variants

EFNB2 p.Cys301Tyr Uncertain significance ★ ⚠ same condition
EFNB2 c.614-8G>A Likely benign same condition
EFNB2 p.Pro261= Likely benign same condition
EFNB2 p.Ser260= Benign same condition
EFNB2 p.Ser38= Likely benign same condition
EFNB2 p.Tyr73Ter Likely pathogenic ★ same type
EFNB2 p.Ala157Thr Uncertain significance ★ ⚠ same type
EFNB2 p.Ala296Ser 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/efnb2-p-leu221 (accessed [today's date]).

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