Is ADNP p.Arg730Gln (c.2189G>A) pathogenic?

ADNP p.Arg730Gln (c.2189G>A) is classified Conflicting classifications of pathogenicity in ADNP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-01-23). AlphaMissense: likely benign (0.2263); Very rare (popmax 0.00424%, nfe); Associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

How common is ADNP p.Arg730Gln (c.2189G>A) in the general population?

ADNP p.Arg730Gln (c.2189G>A) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about ADNP p.Arg730Gln (c.2189G>A)?

AlphaMissense predicts likely benign (score 0.2263) — an in-silico prediction, not a clinical call.

ADNP p.Arg730Gln

Q: What condition is associated with ADNP p.Arg730Gln (c.2189G>A)?

ADNP p.Arg730Gln (c.2189G>A) is associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (ClinVar).

c.2189G>A · rs377051194 · VCV1300622

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.2263	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -6.52	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 4.9	GERP 0.93, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 195 bp · p 0.011 · regional, not allelic
Overall
CADD	23.4	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 0.00424% European (non-Finnish) · 50/1,180,034 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00316% 51/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,601
African / African-American	0.00133%	74,928

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: ADNP
Protein: p.Arg730Gln
Coding: c.2189G>A
MANE Select: NM_001282531
dbSNP: rs377051194
Type: single nucleotide variant
Location: chr20:50892525 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.07

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

Disease context

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADNP p.Arg730Ter Pathogenic/Likely pathogenic ★★ same residue
ADNP p.Arg730fs Pathogenic ★ same residue
ADNP p.Arg730Pro Uncertain significance ★ ⚠ same residue
ADNP p.Arg173Ter Pathogenic ★★ same condition
ADNP p.Arg225Ter Pathogenic/Likely pathogenic ★★ same condition
ADNP p.Ser738Ter Pathogenic ★★ same condition
ADNP p.Trp446Ter Pathogenic ★★ same condition
ADNP p.Tyr172Ter Likely 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/adnp-p-arg730gln (accessed [today's date]).

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