Is ELFN2 p.Pro522Leu (c.1565C>T) pathogenic?

ELFN2 p.Pro522Leu (c.1565C>T) is classified Uncertain significance in ELFN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely benign (0.0867); Ultra-rare (popmax 0.03%, amr).

How common is ELFN2 p.Pro522Leu (c.1565C>T) in the general population?

ELFN2 p.Pro522Leu (c.1565C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about ELFN2 p.Pro522Leu (c.1565C>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

ELFN2 p.Pro522Leu

c.1565C>T · rs376827195 · VCV2518651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -5.28	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 6.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,327 bp · p 0.0019 · regional, not allelic
Overall
CADD	18.87	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 0.03% Admixed American · 18/60,006 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00508% 82/1,612,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
South Asian	0.0143%	7,007
Remaining individualsnot grpmax-eligible	0.0112%	8,924
East Asian	0.00446%	22,439
European (non-Finnish)	0.00347%	28,780
African / African-American	0.00133%	74,928

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: ELFN2
Protein: p.Pro522Leu
Coding: c.1565C>T
MANE Select: NM_052906
dbSNP: rs376827195
Type: single nucleotide variant
Location: chr22:37373970 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 61.79
Residue 522: the 'disordered' region

Full ELFN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ELFN2 p.Asn76Ser Benign ★★ same type
ELFN2 p.Ser262Tyr Benign ★★ same type
ELFN2 p.Ala183Thr Uncertain significance ★ ⚠ same type
ELFN2 p.Ala198Val Uncertain significance ★ ⚠ same type
ELFN2 p.Ala243Gly Uncertain significance ★ ⚠ same type
ELFN2 p.Ala265Thr Uncertain significance ★ ⚠ same type
ELFN2 p.Ala455Thr Uncertain significance ★ ⚠ same type
ELFN2 p.Ala484Thr 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/elfn2-p-pro522leu (accessed [today's date]).

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