Is ENAM p.Ser735= (c.2205T>C) pathogenic?

ENAM p.Ser735= (c.2205T>C) is classified Conflicting classifications of pathogenicity in ENAM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-16). Rare (popmax 0.363%, mid); Associated with amelogenesis imperfecta.

What condition is associated with ENAM p.Ser735= (c.2205T>C)?

ENAM p.Ser735= (c.2205T>C) is associated with amelogenesis imperfecta (ClinVar).

How common is ENAM p.Ser735= (c.2205T>C) in the general population?

ENAM p.Ser735= (c.2205T>C) is rare (popmax 0.363%, mid) (gnomAD).

How is Amelogenesis imperfecta inherited?

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

ENAM p.Ser735=

c.2205T>C · rs144225109 · VCV737651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.363%, mid)

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 -0.62	GERP -3.2, phastCons 0.026
Overall
CADD	2.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.363% Middle Eastern · 22/6,062 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.0836% 1,349/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.363%	276
European (non-Finnish)	0.104%	959
Remaining individualsnot grpmax-eligible	0.0704%	1,421
Admixed American	0.0416%	2,401
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
South Asian	0.011%	9,109
African / African-American	0.00933%	10,722
Finnishnot grpmax-eligible	0.00312%	32,003

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.Ser735=
Coding: c.2205T>C
MANE Select: NM_031889
dbSNP: rs144225109
Type: single nucleotide variant
Location: chr4:70643631 (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-ser735 (accessed [today's date]).

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