Is SHANK3 p.Pro466= (c.1398C>G) pathogenic?

SHANK3 p.Pro466= (c.1398C>G) is classified Conflicting classifications of pathogenicity in SHANK3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2017-08-18). Ultra-rare (popmax 0.02%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SHANK3 p.Pro466= (c.1398C>G)?

SHANK3 p.Pro466= (c.1398C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SHANK3 p.Pro466= (c.1398C>G) in the general population?

SHANK3 p.Pro466= (c.1398C>G) is ultra-rare (popmax 0.02%, nfe) (gnomAD).

SHANK3 p.Pro466=

c.1398C>G · rs371565755 · VCV587761

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP -3.7, phastCons 0.28
Overall
CADD	9.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% European (non-Finnish) · 235/1,176,410 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0152% 244/1,604,180 alleles · ultra-rare exomes 226/1,451,944 · genomes 18/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.02%	5,006
African / African-American	0.00669%	14,955
Remaining individualsnot grpmax-eligible	0.00644%	15,530

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: SHANK3
Protein: p.Pro466=
Coding: c.1398C>G
MANE Select: NM_001372044
dbSNP: rs371565755
Type: single nucleotide variant
Location: chr22:50694917 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.36 · 3 PDB

Full SHANK3 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

SHANK3 p.Arg166Ter Pathogenic/Likely pathogenic ★★ same condition
SHANK3 p.Gln1543Ter Pathogenic/Likely pathogenic ★★ same condition
SHANK3 c.2279G>A Uncertain significance ★★ same condition
SHANK3 p.Ala901Thr Uncertain significance ★★ same condition
SHANK3 p.Arg1298Ser Uncertain significance ★★ same condition
SHANK3 p.Arg1537Cys Uncertain significance ★★ same condition
SHANK3 p.Arg380Cys Uncertain significance ★★ same condition
SHANK3 p.Arg430Gln 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/shank3-p-pro466 (accessed [today's date]).

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