Is ADAM22 p.Ser963Phe (c.2888C>T) pathogenic?

ADAM22 p.Ser963Phe (c.2888C>T) is classified Conflicting classifications of pathogenicity in ADAM22 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-17). AlphaMissense: likely pathogenic (0.9607); Very rare (popmax 0.000763%, nfe); Associated with developmental and epileptic encephalopathy, 61.

What condition is associated with ADAM22 p.Ser963Phe (c.2888C>T)?

ADAM22 p.Ser963Phe (c.2888C>T) is associated with developmental and epileptic encephalopathy, 61 (ClinVar).

How common is ADAM22 p.Ser963Phe (c.2888C>T) in the general population?

ADAM22 p.Ser963Phe (c.2888C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ADAM22 p.Ser963Phe (c.2888C>T)?

AlphaMissense predicts likely pathogenic (score 0.9607) — an in-silico prediction, not a clinical call.

ADAM22 p.Ser963Phe

c.2888C>T · rs2536800069 · VCV1713132

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 61

Computational evidence

Protein change
AlphaMissense	0.9607	likely pathogenic
REVEL	0.29	benign-leaning
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 4.3, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 80 kb · p 2.1e-12 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S905F vs ClinVar S963F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,008 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,770 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: ADAM22
Protein: p.Ser963Phe
Coding: c.2888C>T
MANE Select: NM_001324418
dbSNP: rs2536800069
Type: single nucleotide variant
Location: chr7:88196484 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 10 PDB

Full ADAM22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 61 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAM22 c.1393-3T>C Benign ★★ same condition
ADAM22 c.2596+35T>C Benign ★★ same condition
ADAM22 p.Pro81Arg Benign ★★ same condition
ADAM22 p.Val45Met Benign/Likely benign ★★ ⚠ same condition
ADAM22 c.1617+1G>A Pathogenic ★ same condition
ADAM22 p.Arg954Ter Pathogenic ★ same condition
ADAM22 p.Arg954Gln Uncertain significance ★ ⚠ same condition
ADAM22 p.Gly341Arg 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/adam22-p-ser963phe (accessed [today's date]).

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