Is EFNA3 p.Val71Met (c.211G>A) pathogenic?

EFNA3 p.Val71Met (c.211G>A) is classified Uncertain significance in EFNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely benign (0.0921); Ultra-rare (popmax 0.0356%, mid).

How common is EFNA3 p.Val71Met (c.211G>A) in the general population?

EFNA3 p.Val71Met (c.211G>A) is ultra-rare (popmax 0.0356%, mid) (gnomAD).

What do computational predictors say about EFNA3 p.Val71Met (c.211G>A)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

EFNA3 p.Val71Met

c.211G>A · VCV3843680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -8.93	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 3.2	GERP -1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,598 bp · p 0.15 · regional, not allelic
Overall
CADD	21.8	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 0.0356% Middle Eastern · 2/5,620 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00995%

Overall 0.00193% 30/1,555,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0356%	2,810
African / African-American	0.0201%	4,964
Remaining individualsnot grpmax-eligible	0.0134%	7,477
South Asian	0.00359%	27,859
Admixed American	0.00173%	57,918
European (non-Finnish)	8.79e-05%	1,137,174

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.Val71Met
Coding: c.211G>A
MANE Select: NM_004952
Type: single nucleotide variant
Location: chr1:155085173 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.84
Residue 71: the ephrin rbd domain; a disulfide bond

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-val71met (accessed [today's date]).

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