Is ENAM p.Arg59= (c.177G>T) pathogenic?

ENAM p.Arg59= (c.177G>T) is classified Benign/Likely benign in ENAM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-16). Low-frequency (popmax 3.12%, afr); Associated with amelogenesis imperfecta.

What condition is associated with ENAM p.Arg59= (c.177G>T)?

ENAM p.Arg59= (c.177G>T) is associated with amelogenesis imperfecta (ClinVar).

How common is ENAM p.Arg59= (c.177G>T) in the general population?

ENAM p.Arg59= (c.177G>T) is low-frequency (popmax 3.12%, afr) (gnomAD).

How is Amelogenesis imperfecta inherited?

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

ENAM p.Arg59=

c.177G>T · rs2609429 · VCV716857

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.12%, afr)

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 -0.11	GERP -3.1, phastCons 0.12
Overall
CADD	0.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.12% African / African-American · 2,331/74,728 alleles

Filtering AF 3.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.97%

Overall 0.176% 2,812/1,601,392 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.12%	32
Remaining individualsnot grpmax-eligible	0.226%	443
Admixed American	0.22%	454
Middle Eastern	0.166%	604
European (non-Finnish)	0.0162%	6,184
South Asian	0.011%	9,082

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.Arg59=
Coding: c.177G>T
MANE Select: NM_031889
dbSNP: rs2609429
Type: single nucleotide variant
Location: chr4:70632659 (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

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-arg59 (accessed [today's date]).

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