Is EBI3 p.Leu68Phe (c.202C>T) pathogenic?

EBI3 p.Leu68Phe (c.202C>T) is classified Likely benign in EBI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely benign (0.1264); Very rare (popmax 0.00673%, eas).

How common is EBI3 p.Leu68Phe (c.202C>T) in the general population?

EBI3 p.Leu68Phe (c.202C>T) is very rare (popmax 0.00673%, eas) (gnomAD).

What do computational predictors say about EBI3 p.Leu68Phe (c.202C>T)?

AlphaMissense predicts likely benign (score 0.1264) — an in-silico prediction, not a clinical call.

EBI3 p.Leu68Phe

c.202C>T · VCV4015945

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1264	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.13	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 2	GERP 0.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,534 bp · p 0.34 · regional, not allelic
Overall
CADD	11.81	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 0.00673% East Asian · 3/44,606 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000252% 4/1,589,336 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00673%	14,869
South Asian	0.00112%	88,898

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: EBI3
Protein: p.Leu68Phe
Coding: c.202C>T
MANE Select: NM_005755
Type: single nucleotide variant
Location: chr19:4233130 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.34 · 4 PDB
Residue 68: a β-strand; the fibronectin type-iii 1 domain

Full EBI3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBI3 c.200+3C>T Benign ★★ same type
EBI3 p.Ala13Thr Uncertain significance ★ ⚠ same type
EBI3 p.Ala205Ser Uncertain significance ★ ⚠ same type
EBI3 p.Ala27Val Uncertain significance ★ ⚠ same type
EBI3 p.Arg136Cys Uncertain significance ★ ⚠ same type
EBI3 p.Arg136His Uncertain significance ★ ⚠ same type
EBI3 p.Arg143His Uncertain significance ★ ⚠ same type
EBI3 p.Arg168Cys 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/ebi3-p-leu68phe (accessed [today's date]).

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