Is ENAM p.Arg609= (c.1827G>A) pathogenic?

ENAM p.Arg609= (c.1827G>A) is classified Conflicting classifications of pathogenicity in ENAM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-12). Very rare (popmax 0.00356%, nfe); Associated with amelogenesis imperfecta.

What condition is associated with ENAM p.Arg609= (c.1827G>A)?

ENAM p.Arg609= (c.1827G>A) is associated with amelogenesis imperfecta (ClinVar).

How common is ENAM p.Arg609= (c.1827G>A) in the general population?

ENAM p.Arg609= (c.1827G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

How is Amelogenesis imperfecta inherited?

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

ENAM p.Arg609=

c.1827G>A · rs375265900 · VCV904991

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

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 0.5	GERP -0.061, phastCons 0.92
Overall
CADD	0.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,179,968 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00273% 44/1,613,740 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,094
Admixed American	0.00167%	59,968
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg609=
Coding: c.1827G>A
MANE Select: NM_031889
dbSNP: rs375265900
Type: single nucleotide variant
Location: chr4:70643253 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63
Residue 609: 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-arg609 (accessed [today's date]).

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