Is ERF p.Arg205= (c.615C>G) pathogenic?

ERF p.Arg205= (c.615C>G) is classified Benign in ERF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Arg205= (c.615C>G)?

ERF p.Arg205= (c.615C>G) is associated with TWIST1-related craniosynostosis (ClinVar).

ERF p.Arg205=

Q: How common is ERF p.Arg205= (c.615C>G) in the general population?

ERF p.Arg205= (c.615C>G) is common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.615C>G · rs11557114 · VCV1169687

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 17.6%, mid) — too common for a highly-penetrant pathogenic allele

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 2.2	GERP -2.4, phastCons 1
Overall
CADD	6.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 17.6% Middle Eastern · 1,064/6,052 alleles

Filtering AF 17% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.9%

Overall 7.86% 126,673/1,611,422 alleles · common exomes 115,668/1,459,170 · genomes 11,005/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	17.6%	6
South Asian	17.2%	6
Admixed American	12.3%	8
Ashkenazi Jewishnot grpmax-eligible	9.26%	11
Remaining individualsnot grpmax-eligible	8.71%	11
European (non-Finnish)	7.33%	14
Amishnot grpmax-eligible	5.59%	18
African / African-American	4.97%	20
Finnishnot grpmax-eligible	4.13%	24
East Asian	3.81%	26

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.Arg205=
Coding: c.615C>G
MANE Select: NM_006494
dbSNP: rs11557114
Type: single nucleotide variant
Location: chr19:42249497 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 205: the 'disordered' region; a UniProt-annotated variant site (in)

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.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
ERF p.Arg493His Uncertain significance ★★ ⚠ same condition
ERF p.Lys401Glu 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-arg205 (accessed [today's date]).

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