Is ADNP2 p.Pro423Leu (c.1268C>T) pathogenic?

ADNP2 p.Pro423Leu (c.1268C>T) is classified Uncertain significance in ADNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0994); Ultra-rare (popmax 0.0133%, amr).

How common is ADNP2 p.Pro423Leu (c.1268C>T) in the general population?

ADNP2 p.Pro423Leu (c.1268C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about ADNP2 p.Pro423Leu (c.1268C>T)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

ADNP2 p.Pro423Leu

c.1268C>T · VCV4638532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.39	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 1.7	GERP -0.47, phastCons 0.64
Regional constraint	o/e 1.08	unconstrained · MANE · 20 kb · p 0.032 · regional, not allelic
Overall
CADD	13.79	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 0.0133% Admixed American · 8/59,980 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000496% 8/1,613,112 alleles · ultra-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: ADNP2
Protein: p.Pro423Leu
Coding: c.1268C>T
MANE Select: NM_014913
Type: single nucleotide variant
Location: chr18:80136681 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 58.42

Full ADNP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADNP2 p.Gly54Val Uncertain significance ★★ ⚠ same type
ADNP2 p.Ala222Thr Uncertain significance ★ ⚠ same type
ADNP2 p.Ala271Val Uncertain significance ★ ⚠ same type
ADNP2 p.Ala287Thr Uncertain significance ★ ⚠ same type
ADNP2 p.Ala326Pro Uncertain significance ★ ⚠ same type
ADNP2 p.Ala451Gly Uncertain significance ★ ⚠ same type
ADNP2 p.Ala493Ser Uncertain significance ★ ⚠ same type
ADNP2 p.Ala511Thr Uncertain significance ★ ⚠ 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/adnp2-p-pro423leu (accessed [today's date]).

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