Is ERF p.Val396Ile (c.1186G>A) pathogenic?

ERF p.Val396Ile (c.1186G>A) is classified Likely benign in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1026); Ultra-rare (popmax 0.0154%, sas); Associated with Inborn genetic diseases.

What condition is associated with ERF p.Val396Ile (c.1186G>A)?

ERF p.Val396Ile (c.1186G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERF p.Val396Ile (c.1186G>A) in the general population?

ERF p.Val396Ile (c.1186G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about ERF p.Val396Ile (c.1186G>A)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

ERF p.Val396Ile

c.1186G>A · VCV4250661

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.91	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 1.7	GERP -2.7, phastCons 0.75
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	0.064	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 0.0154% South Asian · 14/91,060 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00162% 26/1,606,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,504
Admixed American	0.00833%	12,000
East Asian	0.00446%	22,433
European (non-Finnish)	0.000424%	235,935

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.Val396Ile
Coding: c.1186G>A
MANE Select: NM_006494
Type: single nucleotide variant
Location: chr19:42248926 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 396: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Gln263Ter Pathogenic ★★ same condition
ERF p.Ala462Pro Uncertain significance ★★ ⚠ same condition
ERF p.Arg179His Uncertain significance ★★ ⚠ same condition
ERF p.Arg233Gln Uncertain significance ★★ ⚠ same condition
ERF p.Arg312Gln Uncertain significance ★★ ⚠ same condition
ERF p.Arg546Ter Uncertain significance ★★ same condition
ERF p.Lys401Glu Uncertain significance ★★ ⚠ same condition
ERF p.Val128Gly 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-val396ile (accessed [today's date]).

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