Is ERF p.Pro285Leu (c.854C>T) pathogenic?

ERF p.Pro285Leu (c.854C>T) is classified Uncertain significance in ERF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-15). AlphaMissense: likely pathogenic (0.6974); Very rare (popmax 8.48e-05%, nfe); Associated with Lambdoidal craniosynostosis.

What condition is associated with ERF p.Pro285Leu (c.854C>T)?

ERF p.Pro285Leu (c.854C>T) is associated with Lambdoidal craniosynostosis (ClinVar).

How common is ERF p.Pro285Leu (c.854C>T) in the general population?

ERF p.Pro285Leu (c.854C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERF p.Pro285Leu (c.854C>T)?

AlphaMissense predicts likely pathogenic (score 0.6974) — an in-silico prediction, not a clinical call.

ERF p.Pro285Leu

c.854C>T · VCV4082075

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Lambdoidal craniosynostosis

Computational evidence

Protein change
AlphaMissense	0.6974	likely pathogenic
REVEL	0.398	indeterminate
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	26.5	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 8.48e-05% European (non-Finnish) · 1/1,179,026 alleles

Overall 0.000657% 1/152,178 alleles · very rare

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.Pro285Leu
Coding: c.854C>T
MANE Select: NM_006494
Type: single nucleotide variant
Location: chr19:42249258 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 285: the 'disordered' region

Full ERF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lambdoidal craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Ser24Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Trp14Ter Likely pathogenic ★★ same condition
ERF p.Arg180Cys Uncertain significance ★★ ⚠ same condition
ERF p.Gln49Ter Likely pathogenic ★ same condition
ERF p.Gly53Ala Likely pathogenic ★ same condition
ERF c.22+2T>G Conflicting classifications of pathogenicity ★ ⚠ same condition
ERF c.373+8C>T Uncertain significance ★ same condition
ERF p.Arg344Gly 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-pro285leu (accessed [today's date]).

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