Is ADNP p.Ser974Arg (c.2922T>A) pathogenic?

ADNP p.Ser974Arg (c.2922T>A) is classified Likely benign in ADNP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.3863); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with ADNP p.Ser974Arg (c.2922T>A)?

ADNP p.Ser974Arg (c.2922T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ADNP p.Ser974Arg (c.2922T>A) in the general population?

ADNP p.Ser974Arg (c.2922T>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ADNP p.Ser974Arg (c.2922T>A)?

AlphaMissense predicts ambiguous (score 0.3863) — an in-silico prediction, not a clinical call.

ADNP p.Ser974Arg

c.2922T>A · rs141643081 · VCV1797728

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3863	ambiguous
REVEL	0.285	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.8
Regional constraint	o/e 1.19	unconstrained · MANE · 812 bp · p 0.00064 · regional, not allelic
Overall
CADD	11.8	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 0.00833% Admixed American · 5/60,008 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00558% 90/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.172%	580
Remaining individualsnot grpmax-eligible	0.0128%	7,813
Admixed Americangrpmax	0.00833%	12,002
South Asian	0.0022%	45,532
European (non-Finnish)	0.00203%	49,166

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser974Arg
Coding: c.2922T>A
MANE Select: NM_001282531
dbSNP: rs141643081
Type: single nucleotide variant
Location: chr20:50891792 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.07
Residue 974: the 'disordered' region

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.Ser974Asn 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
ADNP p.Asn951Ser Uncertain significance ★★ ⚠ same condition
ADNP p.Gln302His 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-ser974arg (accessed [today's date]).

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