Is ADNP p.Ile1069Val (c.3205A>G) pathogenic?

ADNP p.Ile1069Val (c.3205A>G) is classified Uncertain significance in ADNP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0611); Very rare (popmax 0.00212%, nfe); Associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

How common is ADNP p.Ile1069Val (c.3205A>G) in the general population?

ADNP p.Ile1069Val (c.3205A>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about ADNP p.Ile1069Val (c.3205A>G)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

ADNP p.Ile1069Val

Q: What condition is associated with ADNP p.Ile1069Val (c.3205A>G)?

ADNP p.Ile1069Val (c.3205A>G) is associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, intellectual disability (ClinVar).

c.3205A>G · rs1355291048 · VCV2438890

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, 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	0.0611	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.24	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 0.71	GERP 1.8, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 812 bp · p 0.00064 · regional, not allelic
Overall
CADD	13.45	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 0.00212% European (non-Finnish) · 25/1,180,024 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,612,274 alleles · very 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: ADNP
Protein: p.Ile1069Val
Coding: c.3205A>G
MANE Select: NM_001282531
dbSNP: rs1355291048
Type: single nucleotide variant
Location: chr20:50891509 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.07
Residue 1069: the 'disordered' region

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

Disease context

Also linked: intellectual disability

Similar variants

ADNP p.Ile1069Thr Uncertain significance ★★ ⚠ same residue
ADNP p.Ile1069= Likely benign ★★ same residue
ADNP p.Arg173Ter Pathogenic ★★ same condition
ADNP p.Arg216Ter Pathogenic ★★ same condition
ADNP p.Arg225Ter Pathogenic/Likely pathogenic ★★ same condition
ADNP p.Arg730Ter Pathogenic/Likely pathogenic ★★ same condition
ADNP p.Ser738Ter Pathogenic ★★ same condition
ADNP p.Trp446Ter 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-ile1069val (accessed [today's date]).

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