Is EBI3 p.Pro129Ser (c.385C>T) pathogenic?

EBI3 p.Pro129Ser (c.385C>T) is classified Uncertain significance in EBI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely pathogenic (0.9121); Very rare (popmax 0.00223%, eas).

How common is EBI3 p.Pro129Ser (c.385C>T) in the general population?

EBI3 p.Pro129Ser (c.385C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EBI3 p.Pro129Ser (c.385C>T)?

AlphaMissense predicts likely pathogenic (score 0.9121) — an in-silico prediction, not a clinical call.

EBI3 p.Pro129Ser

c.385C>T · rs2512614999 · VCV2269736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9121	likely pathogenic · top 7% in EBI3
REVEL	0.459	indeterminate
SaProt	LLR -11.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,534 bp · p 0.34 · regional, not allelic
Overall
CADD	23.6	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 0.00223% East Asian · 1/44,862 alleles

Overall 6.2e-05% 1/1,612,678 alleles · very rare exomes 1/1,460,324 · genomes 0/152,354 · joint denominator

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.Pro129Ser
Coding: c.385C>T
MANE Select: NM_005755
dbSNP: rs2512614999
Type: single nucleotide variant
Location: chr19:4234672 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.34 · 4 PDB
Residue 129: the fibronectin type-iii 1 domain; an α-helix

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-pro129ser (accessed [today's date]).

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