Is ERF p.Ala410= (c.1230T>C) pathogenic?

ERF p.Ala410= (c.1230T>C) is classified Benign in ERF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 19%, mid) — too common for a highly-penetrant pathogenic allele; Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Ala410= (c.1230T>C)?

ERF p.Ala410= (c.1230T>C) is associated with TWIST1-related craniosynostosis (ClinVar).

ERF p.Ala410=

Q: How common is ERF p.Ala410= (c.1230T>C) in the general population?

ERF p.Ala410= (c.1230T>C) is common (popmax 19%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1230T>C · rs35493131 · VCV1169685

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 19%, 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 -14	GERP -2.6
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19% Middle Eastern · 1,134/5,982 alleles

Filtering AF 18% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.7%

Overall 8.02% 128,846/1,607,094 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	19%	5
South Asian	17.4%	6
Admixed American	12.9%	8
African / African-American	11.6%	9
Remaining individualsnot grpmax-eligible	9.04%	11
Ashkenazi Jewishnot grpmax-eligible	8.83%	11
European (non-Finnish)	7.05%	14
Finnishnot grpmax-eligible	4.04%	25
East Asian	3.79%	26
Amishnot grpmax-eligible	1.1%	91

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.Ala410=
Coding: c.1230T>C
MANE Select: NM_006494
dbSNP: rs35493131
Type: single nucleotide variant
Location: chr19:42248882 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 410: 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.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-ala410 (accessed [today's date]).

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