Is ELFN2 p.Arg616His (c.1847G>A) pathogenic?

ELFN2 p.Arg616His (c.1847G>A) is classified Uncertain significance in ELFN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: likely pathogenic (0.7393); Very rare (popmax 0.000173%, nfe).

How common is ELFN2 p.Arg616His (c.1847G>A) in the general population?

ELFN2 p.Arg616His (c.1847G>A) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about ELFN2 p.Arg616His (c.1847G>A)?

AlphaMissense predicts likely pathogenic (score 0.7393) — an in-silico prediction, not a clinical call.

ELFN2 p.Arg616His

c.1847G>A · rs1332195647 · VCV2473758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7393	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,327 bp · p 0.0019 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000173% European (non-Finnish) · 2/1,159,098 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000128% 2/1,564,860 alleles · very rare

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.Arg616His
Coding: c.1847G>A
MANE Select: NM_052906
dbSNP: rs1332195647
Type: single nucleotide variant
Location: chr22:37373688 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 61.79

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-arg616his (accessed [today's date]).

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