Is EBI3 p.Trp48Arg (c.142T>C) pathogenic?

EBI3 p.Trp48Arg (c.142T>C) is classified Uncertain significance in EBI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.9785); Rare (popmax 0.1%, afr).

How common is EBI3 p.Trp48Arg (c.142T>C) in the general population?

EBI3 p.Trp48Arg (c.142T>C) is rare (popmax 0.1%, afr) (gnomAD).

What do computational predictors say about EBI3 p.Trp48Arg (c.142T>C)?

AlphaMissense predicts likely pathogenic (score 0.9785) — an in-silico prediction, not a clinical call.

EBI3 p.Trp48Arg

c.142T>C · rs368770358 · VCV3086852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9785 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9785	likely pathogenic · top 1% in EBI3
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -15.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,534 bp · p 0.34 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.1% African / African-American · 75/74,850 alleles

Filtering AF 0.0819% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.00527% 85/1,613,278 alleles · rare exomes 40/1,461,112 · genomes 45/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.1%	998
Admixed American	0.00835%	11,972
Remaining individualsnot grpmax-eligible	0.00801%	12,490

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.Trp48Arg
Coding: c.142T>C
MANE Select: NM_005755
dbSNP: rs368770358
Type: single nucleotide variant
Location: chr19:4231265 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.34 · 4 PDB
Residue 48: 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-trp48arg (accessed [today's date]).

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