Is EPHB2 p.Val650Ala (c.1949T>C) pathogenic?

EPHB2 p.Val650Ala (c.1949T>C) is classified Benign in EPHB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.8757); Low-frequency (popmax 1.6%, afr).

How common is EPHB2 p.Val650Ala (c.1949T>C) in the general population?

EPHB2 p.Val650Ala (c.1949T>C) is low-frequency (popmax 1.6%, afr) (gnomAD).

What do computational predictors say about EPHB2 p.Val650Ala (c.1949T>C)?

AlphaMissense predicts likely pathogenic (score 0.8757) — an in-silico prediction, not a clinical call.

EPHB2 p.Val650Ala

c.1949T>C · rs142173175 · VCV786983

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8757 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.6%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8757	likely pathogenic
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -10.03	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 8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 203 kb · p 2.4e-23 · regional, not allelic
Overall
CADD	31.0	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 1.6% African / African-American · 1,200/75,034 alleles

Filtering AF 1.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.49%

Overall 0.0832% 1,343/1,614,172 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.6%	63
Remaining individualsnot grpmax-eligible	0.11%	906
Admixed American	0.0983%	1,017
Middle Eastern	0.0495%	2,021
South Asian	0.00549%	18,214
European (non-Finnish)	0.000593%	168,578

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.Val650Ala
Coding: c.1949T>C
MANE Select: NM_017449
dbSNP: rs142173175
Type: single nucleotide variant
Location: chr1:22906770 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 5 PDB
Residue 650: the protein kinase domain; a UniProt-annotated variant site (in prostate cancer); a β-strand

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

Similar variants

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
EPHB2 p.Ser170= 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-val650ala (accessed [today's date]).

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