Is AMELX p.His84Arg (c.251A>G) pathogenic?

AMELX p.His84Arg (c.251A>G) is classified Uncertain significance in AMELX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2083); Ultra-rare (popmax 0.023%, mid); Associated with Inborn genetic diseases.

What condition is associated with AMELX p.His84Arg (c.251A>G)?

AMELX p.His84Arg (c.251A>G) is associated with Inborn genetic diseases (ClinVar).

How common is AMELX p.His84Arg (c.251A>G) in the general population?

AMELX p.His84Arg (c.251A>G) is ultra-rare (popmax 0.023%, mid) (gnomAD).

What do computational predictors say about AMELX p.His84Arg (c.251A>G)?

AlphaMissense predicts likely benign (score 0.2083) — an in-silico prediction, not a clinical call.

AMELX p.His84Arg

c.251A>G · VCV4090983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2083	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,820 bp · p 8.2e-05 · regional, not allelic
Overall
CADD	22.5	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 0.023% Middle Eastern · 1/4,356 alleles

Overall 9.11e-05% 1/1,098,255 alleles · ultra-rare

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.His84Arg
Coding: c.251A>G
MANE Select: NM_001142
Type: single nucleotide variant
Location: chrX:11298654 (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.Met140Arg Uncertain significance ★ ⚠ same condition
AMELX p.Met57Ile Uncertain significance ★ same condition
AMELX p.Met57Thr Uncertain significance ★ ⚠ same condition
AMELX p.Pro121Leu 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-his84arg (accessed [today's date]).

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