Is ADNP p.Pro131Leu (c.392C>T) pathogenic?

ADNP p.Pro131Leu (c.392C>T) is classified Conflicting classifications of pathogenicity in ADNP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-26). AlphaMissense: ambiguous (0.3908); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with ADNP p.Pro131Leu (c.392C>T)?

ADNP p.Pro131Leu (c.392C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADNP p.Pro131Leu (c.392C>T) in the general population?

ADNP p.Pro131Leu (c.392C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ADNP p.Pro131Leu (c.392C>T)?

AlphaMissense predicts ambiguous (score 0.3908) — an in-silico prediction, not a clinical call.

ADNP p.Pro131Leu

c.392C>T · rs746641833 · VCV1928054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3908	ambiguous
REVEL	0.581	indeterminate
SaProt	LLR -7.65	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 437 bp · p 7.5e-05 · regional, not allelic
Overall
CADD	31.0	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 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00157% 23/1,461,368 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
South Asian	0.0055%	18,188
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,894
European (non-Finnish)	0.0011%	90,761

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.Pro131Leu
Coding: c.392C>T
MANE Select: NM_001282531
dbSNP: rs746641833
Type: single nucleotide variant
Location: chr20:50894322 (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.Pro131= Benign/Likely benign ★★ same residue
ADNP p.Pro131Ser Uncertain significance ★ ⚠ same residue
ADNP p.Pro131Ala Uncertain significance ⚠ same residue
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

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-pro131leu (accessed [today's date]).

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