Is ERF p.Pro199= (c.597G>A) pathogenic?

ERF p.Pro199= (c.597G>A) is classified Likely benign in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-04). Ultra-rare (popmax 0.0107%, afr); Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Pro199= (c.597G>A)?

ERF p.Pro199= (c.597G>A) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Pro199= (c.597G>A) in the general population?

ERF p.Pro199= (c.597G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

ERF p.Pro199=

c.597G>A · rs778540681 · VCV1113783

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.7	GERP -3.4
Overall
CADD	0.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,898 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00205% 33/1,612,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,362
Admixed American	0.00834%	11,986
Finnishnot grpmax-eligible	0.00317%	31,514
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,450
European (non-Finnish)	0.00136%	73,740

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.Pro199=
Coding: c.597G>A
MANE Select: NM_006494
dbSNP: rs778540681
Type: single nucleotide variant
Location: chr19:42249515 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 199: the 'disordered' region

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.Pro199Gln Uncertain significance ★ ⚠ same residue
ERF p.Pro199Leu Uncertain significance ★ ⚠ same residue
ERF p.Arg183Ter Pathogenic ★★ same condition
ERF p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg218Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg86Cys Pathogenic/Likely pathogenic ★★ same condition
ERF p.Ser24Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg458Gly Uncertain significance ★★ ⚠ 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-pro199 (accessed [today's date]).

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