Is EFNB2 p.Pro179Ala (c.535C>G) pathogenic?

EFNB2 p.Pro179Ala (c.535C>G) is classified Uncertain significance in EFNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely benign (0.0649); Ultra-rare (popmax 0.0178%, eas).

How common is EFNB2 p.Pro179Ala (c.535C>G) in the general population?

EFNB2 p.Pro179Ala (c.535C>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about EFNB2 p.Pro179Ala (c.535C>G)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

EFNB2 p.Pro179Ala

c.535C>G · rs746057065 · VCV2356410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,723 bp · p 2.4e-05 · regional, not allelic
Overall
CADD	22.4	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 0.0178% East Asian · 8/44,872 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000547% 8/1,461,824 alleles · ultra-rare

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.Pro179Ala
Coding: c.535C>G
MANE Select: NM_004093
dbSNP: rs746057065
Type: single nucleotide variant
Location: chr13:106494959 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.60 · 10 PDB
Residue 179: the 'disordered' region

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-pro179ala (accessed [today's date]).

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