Is ELFN2 p.Arg516Pro (c.1547G>C) pathogenic?

ELFN2 p.Arg516Pro (c.1547G>C) is classified Uncertain significance in ELFN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.1164); Very rare (popmax 0.0011%, sas).

How common is ELFN2 p.Arg516Pro (c.1547G>C) in the general population?

ELFN2 p.Arg516Pro (c.1547G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ELFN2 p.Arg516Pro (c.1547G>C)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

ELFN2 p.Arg516Pro

c.1547G>C · rs746549719 · VCV3088278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.50	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 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,327 bp · p 0.0019 · regional, not allelic
Overall
CADD	22.5	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 0.0011% South Asian · 1/91,076 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,460,666 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	0.000169%	589,977

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.Arg516Pro
Coding: c.1547G>C
MANE Select: NM_052906
dbSNP: rs746549719
Type: single nucleotide variant
Location: chr22:37373988 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 61.79
Residue 516: 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-arg516pro (accessed [today's date]).

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