Is ADNP p.His222= (c.666C>T) pathogenic?

ADNP p.His222= (c.666C>T) is classified Likely benign in ADNP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0385%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADNP p.His222= (c.666C>T)?

ADNP p.His222= (c.666C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADNP p.His222= (c.666C>T) in the general population?

ADNP p.His222= (c.666C>T) is ultra-rare (popmax 0.0385%, nfe) (gnomAD).

ADNP p.His222=

c.666C>T · rs539414821 · VCV434091

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Overall
CADD	7.955	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% European (non-Finnish) · 454/1,180,048 alleles

Filtering AF 0.0355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0344%

Overall 0.0289% 466/1,614,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0385%	2,599
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Finnishnot grpmax-eligible	0.00625%	16,009
African / African-American	0.004%	24,977
Admixed American	0.00167%	60,012

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.His222=
Coding: c.666C>T
MANE Select: NM_001282531
dbSNP: rs539414821
Type: single nucleotide variant
Location: chr20:50894048 (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

Similar variants

ADNP p.Ser738Ter Pathogenic ★★ same condition
ADNP p.Trp446Ter Pathogenic ★★ same condition
ADNP p.Arg264Gln Uncertain significance ★★ ⚠ same condition
ADNP p.Arg296Gln Uncertain significance ★★ ⚠ same condition
ADNP p.Asn331Tyr Uncertain significance ★★ ⚠ same condition
ADNP p.Asn951Ser Uncertain significance ★★ ⚠ same condition
ADNP p.Gln302His Uncertain significance ★★ ⚠ same condition
ADNP p.Glu1024Val 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/adnp-p-his222 (accessed [today's date]).

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