Is EPHB2 p.Glu532Lys (c.1594G>A) pathogenic?

EPHB2 p.Glu532Lys (c.1594G>A) is classified Uncertain significance in EPHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.7087); Very rare (popmax 0.00329%, sas).

How common is EPHB2 p.Glu532Lys (c.1594G>A) in the general population?

EPHB2 p.Glu532Lys (c.1594G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about EPHB2 p.Glu532Lys (c.1594G>A)?

AlphaMissense predicts likely pathogenic (score 0.7087) — an in-silico prediction, not a clinical call.

EPHB2 p.Glu532Lys

c.1594G>A · VCV4829210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7087	likely pathogenic
REVEL	0.22	benign-leaning
SaProt	LLR -11.37	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 203 kb · p 2.4e-23 · regional, not allelic
Overall
CADD	25.4	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00136% 22/1,614,196 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	75,060
European (non-Finnish)	0.00127%	78,668

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: EPHB2
Protein: p.Glu532Lys
Coding: c.1594G>A
MANE Select: NM_017449
Type: single nucleotide variant
Location: chr1:22895474 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 5 PDB

Full EPHB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB2 p.Glu532Asp Uncertain significance ★ ⚠ same residue
EPHB2 p.Val414Ile Uncertain significance ★★ ⚠ same type
EPHB2 c.1766-9G>T Benign/Likely benign ★★ same type
EPHB2 p.Ala279Ser Benign ★★ same type
EPHB2 p.Asn242= Likely benign ★★ same type
EPHB2 p.Asp574= Benign ★★ same type
EPHB2 p.Asp678Asn Likely benign ★★ same type
EPHB2 p.Gln875= Benign ★★ 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/ephb2-p-glu532lys (accessed [today's date]).

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