Is ADNP2 p.Phe1080Ser (c.3239T>C) pathogenic?

ADNP2 p.Phe1080Ser (c.3239T>C) is classified Uncertain significance in ADNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.8383); Ultra-rare (popmax 0.0165%, mid).

How common is ADNP2 p.Phe1080Ser (c.3239T>C) in the general population?

ADNP2 p.Phe1080Ser (c.3239T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ADNP2 p.Phe1080Ser (c.3239T>C)?

AlphaMissense predicts likely pathogenic (score 0.8383) — an in-silico prediction, not a clinical call.

ADNP2 p.Phe1080Ser

c.3239T>C · rs778709997 · VCV2389631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8383 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8383	likely pathogenic
REVEL	0.512	indeterminate
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 1,556 bp · p 0.14 · regional, not allelic
Overall
CADD	23.5	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.00768% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00599%

Overall 0.00118% 19/1,611,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
South Asian	0.0133%	7,506
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,424
European (non-Finnish)	0.000339%	294,883

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.Phe1080Ser
Coding: c.3239T>C
MANE Select: NM_014913
dbSNP: rs778709997
Type: single nucleotide variant
Location: chr18:80138652 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 58.42
Residue 1080: a DNA-binding region

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-phe1080ser (accessed [today's date]).

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