Is ENAM p.Asn296= (c.888C>T) pathogenic?

ENAM p.Asn296= (c.888C>T) is classified Uncertain significance in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0134%, eas); Associated with amelogenesis imperfecta.

What condition is associated with ENAM p.Asn296= (c.888C>T)?

ENAM p.Asn296= (c.888C>T) is associated with amelogenesis imperfecta (ClinVar).

How common is ENAM p.Asn296= (c.888C>T) in the general population?

ENAM p.Asn296= (c.888C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

How is Amelogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ENAM p.Asn296=

c.888C>T · rs778224567 · VCV349495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

amelogenesis imperfecta

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.08	GERP -2, phastCons 0.001
Overall
CADD	3.599	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,886 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00341% 55/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
Admixed American	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.00339%	29,500
African / African-American	0.00267%	37,453
South Asian	0.0011%	91,088

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
Protein: p.Asn296=
Coding: c.888C>T
MANE Select: NM_031889
dbSNP: rs778224567
Type: single nucleotide variant
Location: chr4:70642314 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63
Residue 296: the 'disordered' region

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

Disease context

amelogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amelogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (United States)

Similar variants

ENAM c.*69T>A Uncertain significance ★★ same condition
ENAM p.Arg939Lys Uncertain significance ★★ ⚠ same condition
ENAM p.Gly631= Uncertain significance ★★ same condition
ENAM p.Ile552Met Uncertain significance ★★ ⚠ same condition
ENAM p.Lys917Gln Uncertain significance ★★ ⚠ same condition
ENAM p.Pro1093Ser Uncertain significance ★★ ⚠ same condition
ENAM c.-123G>A Benign ★★ same condition
ENAM c.*1500G>A Likely benign ★★ 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-p-asn296 (accessed [today's date]).

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