Is EFNB2 p.Val70Ile (c.208G>A) pathogenic?

EFNB2 p.Val70Ile (c.208G>A) is classified Uncertain significance in EFNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.0635); Ultra-rare (popmax 0.0117%, amr).

How common is EFNB2 p.Val70Ile (c.208G>A) in the general population?

EFNB2 p.Val70Ile (c.208G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about EFNB2 p.Val70Ile (c.208G>A)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

EFNB2 p.Val70Ile

c.208G>A · rs373751268 · VCV2399083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 17 kb · p 1.7e-13 · regional, not allelic
Overall
CADD	17.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0117% Admixed American · 7/59,968 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00806% 130/1,613,590 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,567
European (non-Finnish)	0.0101%	9,915
Remaining individualsnot grpmax-eligible	0.0048%	20,822
African / African-American	0.00134%	74,820

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: EFNB2
Protein: p.Val70Ile
Coding: c.208G>A
MANE Select: NM_004093
dbSNP: rs373751268
Type: single nucleotide variant
Location: chr13:106512727 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.60 · 10 PDB
Residue 70: a disulfide bond; the ephrin rbd domain

Full EFNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNB2 p.Tyr73Ter Likely pathogenic ★ same type
EFNB2 p.Ala157Thr Uncertain significance ★ ⚠ same type
EFNB2 p.Ala296Ser Uncertain significance ★ ⚠ same type
EFNB2 p.Arg156Lys Uncertain significance ★ ⚠ same type
EFNB2 p.Arg182His Uncertain significance ★ ⚠ same type
EFNB2 p.Arg253Gln Uncertain significance ★ ⚠ same type
EFNB2 p.Arg253Trp Uncertain significance ★ ⚠ same type
EFNB2 p.Arg277Cys 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/efnb2-p-val70ile (accessed [today's date]).

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