Is ERF p.Leu525fs (c.1569del) pathogenic?

ERF p.Leu525fs (c.1569del) is classified Uncertain significance in ERF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-10). Very rare (popmax 0.00406%, amr).

How common is ERF p.Leu525fs (c.1569del) in the general population?

ERF p.Leu525fs (c.1569del) is very rare (popmax 0.00406%, amr) (gnomAD).

ERF p.Leu525fs

c.1569del · rs1366176199 · VCV451358

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00406%, amr)

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 6.4	GERP 1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00406% Admixed American · 2/49,238 alleles

Filtering AF 0.000982% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000667%

Overall 0.00186% 26/1,396,630 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00406%	24,619
Ashkenazi Jewishnot grpmax-eligible	0.00396%	25,276
South Asian	0.0037%	27,059
Finnishnot grpmax-eligible	0.0033%	30,272
East Asian	0.00226%	44,250
Remaining individualsnot grpmax-eligible	0.00168%	59,528
European (non-Finnish)	0.00139%	71,837

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.Leu525fs
Coding: c.1569del
MANE Select: NM_006494
dbSNP: rs1366176199
Type: Deletion
Location: chr19:42248543 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 525: the 'disordered' region

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

Similar variants

ERF p.Arg143fs Pathogenic/Likely pathogenic ★★ same type
ERF p.Asp188_Cys189insTer Pathogenic ★★ same type
ERF p.Gly299fs Pathogenic/Likely pathogenic ★★ same type
ERF p.Lys401fs Pathogenic/Likely pathogenic ★★ same type
ERF p.Pro133fs Likely pathogenic ★★ same type
ERF p.Pro358fs Pathogenic/Likely pathogenic ★★ same type
ERF p.Ser304del Pathogenic ★★ same type
ERF c.-44_22+11del Pathogenic ★ 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/erf-p-leu525fs (accessed [today's date]).

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