Is ATP6AP2 p.Arg73Gln (c.218G>A) pathogenic?

ATP6AP2 p.Arg73Gln (c.218G>A) is classified Uncertain significance in ATP6AP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0715); Ultra-rare (popmax 0.0282%, mid); Associated with syndromic X-linked intellectual disability Hedera type.

What condition is associated with ATP6AP2 p.Arg73Gln (c.218G>A)?

ATP6AP2 p.Arg73Gln (c.218G>A) is associated with syndromic X-linked intellectual disability Hedera type (ClinVar).

How common is ATP6AP2 p.Arg73Gln (c.218G>A) in the general population?

ATP6AP2 p.Arg73Gln (c.218G>A) is ultra-rare (popmax 0.0282%, mid) (gnomAD).

How is X-linked intellectual disability, Hedera type inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATP6AP2 p.Arg73Gln (c.218G>A)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

ATP6AP2 p.Arg73Gln

c.218G>A · rs138150013 · VCV861472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0282%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Hedera type

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -4.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Pangolin	Δ0.31	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP -0.18, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 25 kb · p 3.4e-09 · regional, not allelic
Overall
CADD	23.4	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 0.0282% Middle Eastern · 1/3,542 alleles

Filtering AF 0.00339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00215%

Overall 0.000827% 10/1,208,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0282%	3,542
African / African-American	0.00875%	11,424
Admixed American	0.00437%	22,859
European (non-Finnish)	0.000223%	447,481

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: ATP6AP2
Protein: p.Arg73Gln
Coding: c.218G>A
MANE Select: NM_005765
dbSNP: rs138150013
Type: single nucleotide variant
Location: chrX:40591283 (GRCh38)
Structure: AlphaFold pLDDT 79.27 · 10 PDB

Full ATP6AP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

syndromic X-linked intellectual disability Hedera type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability, Hedera type (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy

Similar variants

ATP6AP2 p.Arg73Gly Uncertain significance ★ ⚠ same residue
ATP6AP2 p.Arg73Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
ATP6AP2 p.Asp107= Pathogenic ★★ same condition
ATP6AP2 p.Ala259Thr Uncertain significance ★★ ⚠ same condition
ATP6AP2 p.Arg155Cys Uncertain significance ★★ ⚠ same condition
ATP6AP2 p.Arg199His Uncertain significance ★★ ⚠ same condition
ATP6AP2 p.Arg41Gln Uncertain significance ★★ ⚠ same condition
ATP6AP2 p.Asn17Ser 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/atp6ap2-p-arg73gln (accessed [today's date]).

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