Is ADNP p.Ser441Phe (c.1322C>T) pathogenic?

ADNP p.Ser441Phe (c.1322C>T) is classified Likely benign in ADNP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: ambiguous (0.5456); Very rare (popmax 8.47e-05%, nfe).

How common is ADNP p.Ser441Phe (c.1322C>T) in the general population?

ADNP p.Ser441Phe (c.1322C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ADNP p.Ser441Phe (c.1322C>T)?

AlphaMissense predicts ambiguous (score 0.5456) — an in-silico prediction, not a clinical call.

ADNP p.Ser441Phe

c.1322C>T · rs2515585521 · VCV2749600

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5456	ambiguous
REVEL	0.154	moderately benign-leaning
SaProt	LLR -9.30	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 8.2	GERP 0.77, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 438 bp · p 2.4e-12 · regional, not allelic
Overall
CADD	26.0	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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.Ser441Phe
Coding: c.1322C>T
MANE Select: NM_001282531
dbSNP: rs2515585521
Type: single nucleotide variant
Location: chr20:50893392 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.07
Residue 441: the 'disordered' region

Full ADNP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADNP p.Ser441= Uncertain significance ★ same residue
ADNP p.Ser441Tyr Uncertain significance ★ ⚠ same residue
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

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-ser441phe (accessed [today's date]).

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