Is SHANK3 p.Glu1663Ter (c.4987G>T) pathogenic?

SHANK3 p.Glu1663Ter (c.4987G>T) is classified Likely pathogenic in SHANK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). Absent from gnomAD v4.1; Associated with Phelan-McDermid syndrome.

What condition is associated with SHANK3 p.Glu1663Ter (c.4987G>T)?

SHANK3 p.Glu1663Ter (c.4987G>T) is associated with Phelan-McDermid syndrome (ClinVar).

How common is SHANK3 p.Glu1663Ter (c.4987G>T) in the general population?

SHANK3 p.Glu1663Ter (c.4987G>T) is absent from gnomAD v4.1 (gnomAD).

SHANK3 p.Glu1663Ter

c.4987G>T · rs2518439090 · VCV3024516

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,275,800)

Conditions

Phelan-McDermid syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (23 of 23) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.2, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,275,800). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SHANK3
Protein: p.Glu1663Ter
Coding: c.4987G>T
MANE Select: NM_001372044
dbSNP: rs2518439090
Type: single nucleotide variant
Location: chr22:50730878 (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

Phelan-McDermid syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHANK3 c.2455+1G>A Pathogenic ★★ same condition
SHANK3 c.2838C>G Pathogenic ★★ same condition
SHANK3 p.Arg166Ter Pathogenic/Likely pathogenic ★★ same condition
SHANK3 p.Arg432Ter Pathogenic ★★ same condition
SHANK3 p.Asp1564Tyr Pathogenic ★★ same condition
SHANK3 p.Gln1364Ter Pathogenic ★★ same condition
SHANK3 p.Gln1737Ter Pathogenic/Likely pathogenic ★★ same condition
SHANK3 c.1235C>G 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-glu1663ter (accessed [today's date]).

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