Is ERF p.Pro421Leu (c.1262C>T) pathogenic?

ERF p.Pro421Leu (c.1262C>T) is classified Likely benign in ERF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-19). AlphaMissense: likely benign (0.0687); Rare (popmax 0.244%, amr); Associated with Chitayat syndrome.

What condition is associated with ERF p.Pro421Leu (c.1262C>T)?

ERF p.Pro421Leu (c.1262C>T) is associated with Chitayat syndrome, TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Pro421Leu (c.1262C>T) in the general population?

ERF p.Pro421Leu (c.1262C>T) is rare (popmax 0.244%, amr) (gnomAD).

What do computational predictors say about ERF p.Pro421Leu (c.1262C>T)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

ERF p.Pro421Leu

c.1262C>T · rs533363033 · VCV800173

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.244%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Chitayat syndrome

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.47	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 4.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	21.4	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 0.244% Admixed American · 146/59,926 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.0128% 206/1,610,318 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.244%	410
Remaining individualsnot grpmax-eligible	0.0112%	8,913
Finnishnot grpmax-eligible	0.00811%	12,335
European (non-Finnish)	0.00382%	26,199
South Asian	0.0033%	30,331

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.Pro421Leu
Coding: c.1262C>T
MANE Select: NM_006494
dbSNP: rs533363033
Type: single nucleotide variant
Location: chr19:42248850 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 421: the 'disordered' region

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

Disease context

Chitayat syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: TWIST1-related craniosynostosis

Similar variants

ERF p.Pro421= 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.Tyr89Cys Pathogenic ★★ same condition
ERF p.Arg180Cys 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-pro421leu (accessed [today's date]).

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