Is ADNP p.Arg94Cys (c.280C>T) pathogenic?

ADNP p.Arg94Cys (c.280C>T) is classified Uncertain significance in ADNP (ClinVar, Single submitter, 2 submitters; last evaluated 2026-02-20). AlphaMissense: likely pathogenic (0.9778); Very rare (popmax 8.48e-05%, nfe); Associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

How common is ADNP p.Arg94Cys (c.280C>T) in the general population?

ADNP p.Arg94Cys (c.280C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ADNP p.Arg94Cys (c.280C>T)?

AlphaMissense predicts likely pathogenic (score 0.9778) — an in-silico prediction, not a clinical call.

ADNP p.Arg94Cys

Q: What condition is associated with ADNP p.Arg94Cys (c.280C>T)?

ADNP p.Arg94Cys (c.280C>T) is associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (ClinVar).

c.280C>T · rs1186714720 · VCV975321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9778	likely pathogenic
REVEL	0.672	pathogenic-leaning
SaProt	LLR -8.74	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 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 102 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,804 alleles

Overall 6.84e-05% 1/1,461,046 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.Arg94Cys
Coding: c.280C>T
MANE Select: NM_001282531
dbSNP: rs1186714720
Type: single nucleotide variant
Location: chr20:50894434 (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.Arg94His 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-arg94cys (accessed [today's date]).

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