Is ADNP2 p.Ser677Ala (c.2029T>G) pathogenic?

ADNP2 p.Ser677Ala (c.2029T>G) is classified Likely benign in ADNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely benign (0.0765); Rare (popmax 0.897%, nfe).

How common is ADNP2 p.Ser677Ala (c.2029T>G) in the general population?

ADNP2 p.Ser677Ala (c.2029T>G) is rare (popmax 0.897%, nfe) (gnomAD).

What do computational predictors say about ADNP2 p.Ser677Ala (c.2029T>G)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

ADNP2 p.Ser677Ala

c.2029T>G · VCV3770466

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.897%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -6.02	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 -1.5	GERP -3.1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,556 bp · p 0.14 · regional, not allelic
Overall
CADD	0.041	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 0.897% European (non-Finnish) · 10,587/1,180,016 alleles

Filtering AF 0.883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.877%

Overall 0.713% 11,511/1,614,118 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.897%	111
Remaining individualsnot grpmax-eligible	0.809%	124
Admixed American	0.227%	441
Finnishnot grpmax-eligible	0.192%	520
Middle Eastern	0.149%	673
African / African-American	0.133%	750
East Asian	0.0869%	1,151
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
South Asian	0.00549%	18,215

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.Ser677Ala
Coding: c.2029T>G
MANE Select: NM_014913
Type: single nucleotide variant
Location: chr18:80137442 (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-ser677ala (accessed [today's date]).

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