Is ERF p.Ala254= (c.762C>T) pathogenic?

ERF p.Ala254= (c.762C>T) is classified Likely benign in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-05). Ultra-rare (popmax 0.0149%, amr); Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Ala254= (c.762C>T)?

ERF p.Ala254= (c.762C>T) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Ala254= (c.762C>T) in the general population?

ERF p.Ala254= (c.762C>T) is ultra-rare (popmax 0.0149%, amr) (gnomAD).

ERF p.Ala254=

c.762C>T · rs774421092 · VCV2022405

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, amr)

Conditions

TWIST1-related craniosynostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.4	GERP -3.7
Overall
CADD	0.125	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0149% Admixed American · 8/53,694 alleles

Filtering AF 0.00738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00541%

Overall 0.000912% 13/1,425,446 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0149%	6,712
European (non-Finnish)	0.00043%	232,475

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.Ala254=
Coding: c.762C>T
MANE Select: NM_006494
dbSNP: rs774421092
Type: single nucleotide variant
Location: chr19:42249350 (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.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-ala254 (accessed [today's date]).

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