Is ADNP p.Phe741Cys (c.2222T>G) pathogenic?

ADNP p.Phe741Cys (c.2222T>G) is classified Uncertain significance in ADNP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0618); Very rare (popmax 0.00167%, amr).

How common is ADNP p.Phe741Cys (c.2222T>G) in the general population?

ADNP p.Phe741Cys (c.2222T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ADNP p.Phe741Cys (c.2222T>G)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

ADNP p.Phe741Cys

c.2222T>G · rs1197817691 · VCV2159549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.33	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 1.2	GERP -3.8, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 195 bp · p 0.011 · regional, not allelic
Overall
CADD	18.02	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.00136%	73,753
South Asian	0.0011%	91,086

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.Phe741Cys
Coding: c.2222T>G
MANE Select: NM_001282531
dbSNP: rs1197817691
Type: single nucleotide variant
Location: chr20:50892492 (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

Similar variants

ADNP p.Phe741Leu Uncertain significance ★ ⚠ same residue
ADNP p.Arg173Ter Pathogenic ★★ same type
ADNP p.Arg216Ter Pathogenic ★★ same type
ADNP p.Arg225Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Arg306Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Arg730Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Ser738Ter Pathogenic ★★ same type
ADNP p.Trp446Ter Pathogenic ★★ same type

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-phe741cys (accessed [today's date]).

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