Is ADNP p.Ser265Cys (c.794C>G) pathogenic?

ADNP p.Ser265Cys (c.794C>G) is classified Uncertain significance in ADNP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely benign (0.2624); Very rare (popmax 0.00667%, amr).

How common is ADNP p.Ser265Cys (c.794C>G) in the general population?

ADNP p.Ser265Cys (c.794C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ADNP p.Ser265Cys (c.794C>G)?

AlphaMissense predicts likely benign (score 0.2624) — an in-silico prediction, not a clinical call.

ADNP p.Ser265Cys

c.794C>G · VCV3701028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2624	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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 1.12	unconstrained · MANE · 536 bp · p 0.077 · regional, not allelic
Overall
CADD	27.0	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 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ser265Cys
Coding: c.794C>G
MANE Select: NM_001282531
Type: single nucleotide variant
Location: chr20:50893920 (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

Similar variants

ADNP p.Arg173Ter Pathogenic ★★ same type
ADNP p.Arg216Ter Pathogenic ★★ same type
ADNP p.Arg225Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Arg306Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Arg730Ter Pathogenic/Likely pathogenic ★★ same type
ADNP p.Ser738Ter Pathogenic ★★ same type
ADNP p.Trp446Ter Pathogenic ★★ same type
ADNP p.Tyr172Ter Likely pathogenic ★★ 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/adnp-p-ser265cys (accessed [today's date]).

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