Is ERF p.Arg86Cys (c.256C>T) pathogenic?

ERF p.Arg86Cys (c.256C>T) is classified Pathogenic/Likely pathogenic in ERF (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 8.48e-05%, nfe); Associated with ERF-related disorder.

What condition is associated with ERF p.Arg86Cys (c.256C>T)?

ERF p.Arg86Cys (c.256C>T) is associated with ERF-related disorder, TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Arg86Cys (c.256C>T) in the general population?

ERF p.Arg86Cys (c.256C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERF p.Arg86Cys (c.256C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

ERF p.Arg86Cys

c.256C>T · rs587777008 · VCV55925

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ERF-related disorder

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 5% in ERF
REVEL	0.765	pathogenic-leaning
SaProt	LLR -16.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP -0.73, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 558 bp · p 2.8e-12 · regional, not allelic
Overall
CADD	35.0	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) · 1/1,179,832 alleles

Overall 6.84e-05% 1/1,461,414 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.Arg86Cys
Coding: c.256C>T
MANE Select: NM_006494
dbSNP: rs587777008
Type: single nucleotide variant
Location: chr19:42250332 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 86: a DNA-binding region; a UniProt-annotated variant site (in crs4); an α-helix

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

Disease context

ERF-related disorder

Also linked: TWIST1-related craniosynostosis

Similar variants

ERF p.Arg86His Conflicting classifications of pathogenicity ★ ⚠ 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.Arg233Ter Pathogenic ★★ same condition
ERF p.Gly53Arg Likely pathogenic ★★ same condition
ERF p.Ser24Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Tyr89Cys Pathogenic ★★ 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-arg86cys (accessed [today's date]).

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