Is ERF p.Ser171del (c.498_500del) pathogenic?

ERF p.Ser171del (c.498500del) is classified Uncertain significance in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). Ultra-rare (popmax 0.0255%, nfe); Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Ser171del (c.498_500del)?

ERF p.Ser171del (c.498_500del) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Ser171del (c.498_500del) in the general population?

ERF p.Ser171del (c.498_500del) is ultra-rare (popmax 0.0255%, nfe) (gnomAD).

ERF p.Ser171del

c.498_500del · VCV3678477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0255%, nfe)

Conditions

TWIST1-related craniosynostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0255% European (non-Finnish) · 301/1,179,714 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0201% 324/1,612,804 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0336%	2,974
European (non-Finnish)grpmax	0.0255%	3,919
Admixed American	0.00167%	59,888
African / African-American	0.00134%	74,610

Remaining individuals 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.Ser171del
Coding: c.498_500del
MANE Select: NM_006494
Type: Deletion
Location: chr19:42249612 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB

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

Disease context

TWIST1-related craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Arg143fs Pathogenic/Likely pathogenic ★★ same condition
ERF p.Asp188_Cys189insTer Pathogenic ★★ same condition
ERF p.Gly299fs Pathogenic/Likely pathogenic ★★ same condition
ERF p.Lys401fs Pathogenic/Likely pathogenic ★★ same condition
ERF p.Pro358fs Pathogenic/Likely pathogenic ★★ same condition
ERF p.Ser304del Pathogenic ★★ same condition
ERF c.-44_22+11del Pathogenic ★ same condition
ERF p.Gln341fs 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-ser171del (accessed [today's date]).

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