Is ENAM c.588+1del pathogenic?

ENAM c.588+1del is classified Pathogenic in ENAM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-11). Very rare (popmax 0.000425%, nfe); Associated with ENAM-related disorder.

What condition is associated with ENAM c.588+1del?

ENAM c.588+1del is associated with ENAM-related disorder, amelogenesis imperfecta type 1B (ClinVar).

How common is ENAM c.588+1del in the general population?

ENAM c.588+1del is very rare (popmax 0.000425%, nfe) (gnomAD).

ENAM c.588+1del

rs752102959 · VCV1192504

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Conditions

ENAM-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.19	GERP -0.72, phastCons 0.29
Non-coding constraint	Z -0.72	1 kb window · o/e 1.06 · regional · uncalibrated

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,177,024 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,458,620 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: ENAM
Coding: c.588+1del
MANE Select: NM_031889
dbSNP: rs752102959
Type: Deletion
Location: chr4:70637838 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63

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

Disease context

ENAM-related disorder

Also linked: amelogenesis imperfecta type 1B

Similar variants

ENAM p.Asp921fs Pathogenic/Likely pathogenic ★★ same condition
ENAM p.Asn36fs Likely pathogenic ★ same condition
ENAM p.Asn628fs Likely pathogenic ★ same condition
ENAM c.588+1dup Pathogenic/Likely pathogenic ★★ same condition
ENAM p.Pro422fs Pathogenic/Likely pathogenic ★★ same condition
ENAM p.Leu34Pro Uncertain significance ★★ ⚠ same condition
ENAM p.Gln222Ter Pathogenic ★ same condition
ENAM p.Glu218Ter Likely 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/enam-c-588-plus-1del (accessed [today's date]).

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