Is ERF p.Glu516fs (c.1546del) pathogenic?

ERF p.Glu516fs (c.1546del) is classified Uncertain significance in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-22). Very rare (popmax 8.66e-05%, nfe); Associated with Paediatric disorders.

What condition is associated with ERF p.Glu516fs (c.1546del)?

ERF p.Glu516fs (c.1546del) is associated with Paediatric disorders (ClinVar).

How common is ERF p.Glu516fs (c.1546del) in the general population?

ERF p.Glu516fs (c.1546del) is very rare (popmax 8.66e-05%, nfe) (gnomAD).

ERF p.Glu516fs

c.1546del · VCV4820640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.66e-05%, nfe)

Conditions

Paediatric disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.66e-05% European (non-Finnish) · 1/1,155,228 alleles

Overall 0.000142% 2/1,413,304 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00162%	61,642
European (non-Finnish)grpmax	8.66e-05%	1,155,228

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ERF
Protein: p.Glu516fs
Coding: c.1546del
MANE Select: NM_006494
Type: Deletion
Location: chr19:42248566 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 516: the 'disordered' region

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

Disease context

Paediatric disorders

Similar variants

ERF p.Asp6fs Likely pathogenic ★ same condition
ERF p.Phe504fs Pathogenic ★ same condition
ERF p.Pro4fs Pathogenic ★ same condition
ERF p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg218Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg233Ter Pathogenic ★★ same condition
ERF p.Arg86Cys Pathogenic/Likely pathogenic ★★ same condition
ERF p.Gly53Arg Likely pathogenic ★★ same condition

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/erf-p-glu516fs (accessed [today's date]).

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