Is ADNP2 p.Ala733Ser (c.2197G>T) pathogenic?

ADNP2 p.Ala733Ser (c.2197G>T) is classified Uncertain significance in ADNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.5789); Very rare (popmax 0.005%, amr).

How common is ADNP2 p.Ala733Ser (c.2197G>T) in the general population?

ADNP2 p.Ala733Ser (c.2197G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ADNP2 p.Ala733Ser (c.2197G>T)?

AlphaMissense predicts likely pathogenic (score 0.5789) — an in-silico prediction, not a clinical call.

ADNP2 p.Ala733Ser

c.2197G>T · rs750640679 · VCV2234266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5789	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,556 bp · p 0.14 · regional, not allelic
Overall
CADD	24.5	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 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.000254%	393,352

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.Ala733Ser
Coding: c.2197G>T
MANE Select: NM_014913
dbSNP: rs750640679
Type: single nucleotide variant
Location: chr18:80137610 (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-ala733ser (accessed [today's date]).

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