Is EPHB3 p.Thr613Ile (c.1838C>T) pathogenic?

EPHB3 p.Thr613Ile (c.1838C>T) is classified Uncertain significance in EPHB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9839); Rare (popmax 0.203%, afr).

How common is EPHB3 p.Thr613Ile (c.1838C>T) in the general population?

EPHB3 p.Thr613Ile (c.1838C>T) is rare (popmax 0.203%, afr) (gnomAD).

What do computational predictors say about EPHB3 p.Thr613Ile (c.1838C>T)?

AlphaMissense predicts likely pathogenic (score 0.9839) — an in-silico prediction, not a clinical call.

EPHB3 p.Thr613Ile

c.1838C>T · rs147540989 · VCV2215302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9839 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.203%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9839	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -14.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	29.9	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 0.203% African / African-American · 152/75,006 alleles

Filtering AF 0.176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.00998% 161/1,614,030 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.203%	493
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.005%	20,003

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: EPHB3
Protein: p.Thr613Ile
Coding: c.1838C>T
MANE Select: NM_004443
dbSNP: rs147540989
Type: single nucleotide variant
Location: chr3:184579513 (GRCh38)
Gene constraint: LOEUF 0.435 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.62 · 4 PDB

Full EPHB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB3 c.1748+4C>T Benign ★★ same type
EPHB3 p.Phe689= Benign ★★ same type
EPHB3 p.Pro438= Benign ★★ same type
EPHB3 p.Ala220Thr Uncertain significance ★ ⚠ same type
EPHB3 p.Ala229Val Uncertain significance ★ ⚠ same type
EPHB3 p.Ala315Thr Uncertain significance ★ ⚠ same type
EPHB3 p.Ala332Val Uncertain significance ★ ⚠ same type
EPHB3 p.Ala442Glu 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/ephb3-p-thr613ile (accessed [today's date]).

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