Is EFNA3 p.Pro64Ala (c.190C>G) pathogenic?

EFNA3 p.Pro64Ala (c.190C>G) is classified Uncertain significance in EFNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.9938); Very rare (popmax 0.00133%, afr).

How common is EFNA3 p.Pro64Ala (c.190C>G) in the general population?

EFNA3 p.Pro64Ala (c.190C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EFNA3 p.Pro64Ala (c.190C>G)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

EFNA3 p.Pro64Ala

c.190C>G · VCV3507029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -13.67	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,598 bp · p 0.15 · regional, not allelic
Overall
CADD	29.3	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 0.00133% African / African-American · 1/74,932 alleles

Overall 6.2e-05% 1/1,613,450 alleles · very rare exomes 0/1,461,236 · genomes 1/152,214 · joint denominator

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: EFNA3
Protein: p.Pro64Ala
Coding: c.190C>G
MANE Select: NM_004952
Type: single nucleotide variant
Location: chr1:155085152 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.84
Residue 64: the ephrin rbd domain

Full EFNA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNA3 p.Ser133= Benign ★★ same type
EFNA3 p.Ala101Ser Uncertain significance ★ ⚠ same type
EFNA3 p.Ala168Val Uncertain significance ★ ⚠ same type
EFNA3 p.Arg219Gln Uncertain significance ★ ⚠ same type
EFNA3 p.Arg219Trp Uncertain significance ★ ⚠ same type
EFNA3 p.Arg45Trp Uncertain significance ★ ⚠ same type
EFNA3 p.Asn193Asp Uncertain significance ★ ⚠ same type
EFNA3 p.Asp57Glu 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/efna3-p-pro64ala (accessed [today's date]).

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