Is ERF p.Leu275Pro (c.824T>C) pathogenic?

ERF p.Leu275Pro (c.824T>C) is classified Conflicting classifications of pathogenicity in ERF (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: likely benign (0.2695); Ultra-rare (popmax 0.0993%, mid); Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Leu275Pro (c.824T>C)?

ERF p.Leu275Pro (c.824T>C) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Leu275Pro (c.824T>C) in the general population?

ERF p.Leu275Pro (c.824T>C) is ultra-rare (popmax 0.0993%, mid) (gnomAD).

What do computational predictors say about ERF p.Leu275Pro (c.824T>C)?

AlphaMissense predicts likely benign (score 0.2695) — an in-silico prediction, not a clinical call.

ERF p.Leu275Pro

c.824T>C · rs756557668 · VCV1043453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0993%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TWIST1-related craniosynostosis

Computational evidence

Protein change
AlphaMissense	0.2695	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0993% Middle Eastern · 6/6,040 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00249% 40/1,603,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0993%	1,007
Remaining individualsnot grpmax-eligible	0.00806%	12,412
Admixed American	0.00345%	28,965
South Asian	0.00222%	45,141
European (non-Finnish)	0.00204%	48,976
African / African-American	0.00134%	74,566

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.Leu275Pro
Coding: c.824T>C
MANE Select: NM_006494
dbSNP: rs756557668
Type: single nucleotide variant
Location: chr19:42249288 (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.Leu275= Likely benign ★ 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
ERF p.Arg493His 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-leu275pro (accessed [today's date]).

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