Is ADNP p.Ile221Ser (c.662T>G) pathogenic?

ADNP p.Ile221Ser (c.662T>G) is classified Conflicting classifications of pathogenicity in ADNP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-07). AlphaMissense: likely pathogenic (0.787); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with ADNP p.Ile221Ser (c.662T>G)?

ADNP p.Ile221Ser (c.662T>G) is associated with Inborn genetic diseases, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (ClinVar).

How common is ADNP p.Ile221Ser (c.662T>G) in the general population?

ADNP p.Ile221Ser (c.662T>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ADNP p.Ile221Ser (c.662T>G)?

AlphaMissense predicts likely pathogenic (score 0.787) — an in-silico prediction, not a clinical call.

ADNP p.Ile221Ser

c.662T>G · rs747105829 · VCV1679675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.787	likely pathogenic
REVEL	0.698	pathogenic-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 437 bp · p 7.5e-05 · regional, not allelic
Overall
CADD	26.3	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 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00149% 24/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.00329%	30,365
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,940
European (non-Finnish)	0.0011%	90,770

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.Ile221Ser
Coding: c.662T>G
MANE Select: NM_001282531
dbSNP: rs747105829
Type: single nucleotide variant
Location: chr20:50894052 (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

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

Also linked: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Similar variants

ADNP p.Ile221Val Uncertain significance ★ ⚠ same residue
ADNP p.Arg173Ter 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
ADNP p.Tyr172Ter Likely pathogenic ★★ same condition
ADNP p.Tyr378Ter 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-ile221ser (accessed [today's date]).

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