Is AMELX p.Val94Met (c.280G>A) pathogenic?

AMELX p.Val94Met (c.280G>A) is classified Uncertain significance in AMELX (ClinVar, Single submitter, 1 submitter; last evaluated 2015-06-12). AlphaMissense: likely benign (0.0724); Very rare (popmax 0.00503%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMELX p.Val94Met (c.280G>A)?

AMELX p.Val94Met (c.280G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AMELX p.Val94Met (c.280G>A) in the general population?

AMELX p.Val94Met (c.280G>A) is very rare (popmax 0.00503%, nfe) (gnomAD).

What do computational predictors say about AMELX p.Val94Met (c.280G>A)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

AMELX p.Val94Met

c.280G>A · rs373800800 · VCV520691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.68, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,820 bp · p 8.2e-05 · regional, not allelic
Overall
CADD	15.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00503% European (non-Finnish) · 45/894,843 alleles

Filtering AF 0.00383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00342%

Overall 0.00397% 48/1,208,188 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00503%	19,885
African / African-American	0.00354%	28,243
Remaining individualsnot grpmax-eligible	0.0021%	47,574

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.Val94Met
Coding: c.280G>A
MANE Select: NM_001142
dbSNP: rs373800800
Type: single nucleotide variant
Location: chrX:11298683 (GRCh38)
Structure: AlphaFold pLDDT 59.51

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMELX c.103-111A>G Uncertain significance ★★ same condition
AMELX p.Arg187Gln Uncertain significance ★ ⚠ same condition
AMELX p.Arg187Gly Uncertain significance ★ ⚠ same condition
AMELX p.His77Tyr Uncertain significance ★ ⚠ same condition
AMELX p.His84Arg Uncertain significance ★ ⚠ same condition
AMELX p.Met140Arg Uncertain significance ★ ⚠ same condition
AMELX p.Met57Ile Uncertain significance ★ ⚠ same condition
AMELX p.Met57Thr Uncertain significance ★ ⚠ 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-val94met (accessed [today's date]).

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