Is ERF p.Arg86His (c.257G>A) pathogenic?

ERF p.Arg86His (c.257G>A) is classified Conflicting classifications of pathogenicity in ERF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-11). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Arg86His (c.257G>A)?

ERF p.Arg86His (c.257G>A) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Arg86His (c.257G>A) in the general population?

ERF p.Arg86His (c.257G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERF p.Arg86His (c.257G>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

ERF p.Arg86His

c.257G>A · rs765295141 · VCV946328

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TWIST1-related craniosynostosis

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 5% in ERF
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -15.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Pangolin	Δ0.48	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 558 bp · p 2.8e-12 · regional, not allelic
Overall
CADD	36.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERF
Protein: p.Arg86His
Coding: c.257G>A
MANE Select: NM_006494
dbSNP: rs765295141
Type: single nucleotide variant
Location: chr19:42250331 (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

TWIST1-related craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Arg86Cys Pathogenic/Likely pathogenic ★★ 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.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-arg86his (accessed [today's date]).

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