Is EFNA2 p.Pro194Ser (c.580C>T) pathogenic?

EFNA2 p.Pro194Ser (c.580C>T) is classified Uncertain significance in EFNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0695); Rare (popmax 0.111%, sas).

How common is EFNA2 p.Pro194Ser (c.580C>T) in the general population?

EFNA2 p.Pro194Ser (c.580C>T) is rare (popmax 0.111%, sas) (gnomAD).

What do computational predictors say about EFNA2 p.Pro194Ser (c.580C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

EFNA2 p.Pro194Ser

c.580C>T · VCV4247110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.54	GERP -1.6, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.68 · regional, not allelic
Overall
CADD	5.501	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 0.111% South Asian · 100/90,356 alleles

Filtering AF 0.0931% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0865%

Overall 0.00648% 104/1,604,542 alleles · rare exomes 95/1,452,216 · genomes 9/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.111%	904
Remaining individualsnot grpmax-eligible	0.00482%	20,737
East Asian	0.00224%	44,736

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: EFNA2
Protein: p.Pro194Ser
Coding: c.580C>T
MANE Select: NM_001405
Type: single nucleotide variant
Location: chr19:1299883 (GRCh38)
Gene constraint: LOEUF 1.447 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00 · 1 PDB

Full EFNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNA2 p.Pro194Arg Uncertain significance ★ ⚠ same residue
EFNA2 p.Pro194Leu Likely benign ★ same residue
EFNA2 p.Ala180Thr Uncertain significance ★ ⚠ same type
EFNA2 p.Arg105His Uncertain significance ★ ⚠ same type
EFNA2 p.Arg161Gln Uncertain significance ★ ⚠ same type
EFNA2 p.Arg171Trp Uncertain significance ★ same type
EFNA2 p.Arg43Leu Uncertain significance ★ same type
EFNA2 p.Arg6Pro 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/efna2-p-pro194ser (accessed [today's date]).

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