Is AMELX p.Trp4Ser (c.11G>C) pathogenic?

AMELX p.Trp4Ser (c.11G>C) is classified Pathogenic in AMELX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2004-05-01). AlphaMissense: ambiguous (0.4573); Very rare (popmax 0.000112%, nfe); Associated with amelogenesis imperfecta type 1E.

What condition is associated with AMELX p.Trp4Ser (c.11G>C)?

AMELX p.Trp4Ser (c.11G>C) is associated with amelogenesis imperfecta type 1E (ClinVar).

How common is AMELX p.Trp4Ser (c.11G>C) in the general population?

AMELX p.Trp4Ser (c.11G>C) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about AMELX p.Trp4Ser (c.11G>C)?

AlphaMissense predicts ambiguous (score 0.4573) — an in-silico prediction, not a clinical call.

AMELX p.Trp4Ser

c.11G>C · rs104894738 · VCV11146

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

amelogenesis imperfecta type 1E

Computational evidence

Protein change
AlphaMissense	0.4573	ambiguous
REVEL	0.511	indeterminate
SaProt	LLR -6.11	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,820 bp · p 8.2e-05 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/895,426 alleles

Overall 8.25e-05% 1/1,211,761 alleles · very rare exomes 1/1,098,108 · genomes 0/113,653 · joint denominator

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: AMELX
Protein: p.Trp4Ser
Coding: c.11G>C
MANE Select: NM_001142
dbSNP: rs104894738
Type: single nucleotide variant
Location: chrX:11294799 (GRCh38)
Structure: AlphaFold pLDDT 59.51
Residue 4: a UniProt-annotated variant site (in ai1e)

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

Disease context

amelogenesis imperfecta type 1E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMELX p.Trp4Ter Likely pathogenic ★ same residue
AMELX p.Met1Ile Likely pathogenic ★★ same condition
AMELX p.Pro56Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
AMELX c.103-111A>G Uncertain significance ★★ same condition
AMELX c.144+1G>A Likely pathogenic ★ same condition
AMELX p.Glu177Ter Pathogenic same condition
AMELX p.Thr37Ile Pathogenic ⚠ same condition
AMELX p.Ile5_Ala8delinsThr 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/amelx-p-trp4ser (accessed [today's date]).

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