Is ERF p.Ala415Val (c.1244C>T) pathogenic?

ERF p.Ala415Val (c.1244C>T) is classified Benign/Likely benign in ERF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0762); Low-frequency (popmax 2%, nfe); Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Ala415Val (c.1244C>T)?

ERF p.Ala415Val (c.1244C>T) is associated with TWIST1-related craniosynostosis (ClinVar).

How common is ERF p.Ala415Val (c.1244C>T) in the general population?

ERF p.Ala415Val (c.1244C>T) is low-frequency (popmax 2%, nfe) (gnomAD).

What do computational predictors say about ERF p.Ala415Val (c.1244C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

ERF p.Ala415Val

c.1244C>T · rs139842507 · VCV476625

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TWIST1-related craniosynostosis

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -8.11	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 1.4	GERP -1, phastCons 0.008
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	5.653	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 2% European (non-Finnish) · 23,571/1,178,332 alleles

Filtering AF 1.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 1.74% 27,914/1,607,218 alleles · low-frequency exomes 26,133/1,455,028 · genomes 1,781/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2%	50
Finnishnot grpmax-eligible	1.91%	52
Remaining individualsnot grpmax-eligible	1.52%	66
East Asian	1.29%	77
South Asian	0.968%	103
Ashkenazi Jewishnot grpmax-eligible	0.655%	153
Admixed American	0.598%	167
African / African-American	0.3%	333
Middle Eastern	0.282%	354

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.Ala415Val
Coding: c.1244C>T
MANE Select: NM_006494
dbSNP: rs139842507
Type: single nucleotide variant
Location: chr19:42248868 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 415: the 'disordered' region

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.Ala415= Likely benign ★ same residue
ERF p.Ala415del Uncertain significance ★ 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

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-ala415val (accessed [today's date]).

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