Is SHANK2 p.Pro655Ser (c.1963C>T) pathogenic?

SHANK2 p.Pro655Ser (c.1963C>T) is classified Uncertain significance in SHANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). AlphaMissense: likely pathogenic (0.9751); Absent from gnomAD v4.1.

How common is SHANK2 p.Pro655Ser (c.1963C>T) in the general population?

SHANK2 p.Pro655Ser (c.1963C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SHANK2 p.Pro655Ser (c.1963C>T)?

AlphaMissense predicts likely pathogenic (score 0.9751) — an in-silico prediction, not a clinical call.

SHANK2 p.Pro655Ser

c.1963C>T · rs2497976364 · VCV3026648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9751 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.9751	likely pathogenic · top 6% in SHANK2
REVEL	0.453	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,746 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P276S vs ClinVar P655S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SHANK2
Protein: p.Pro655Ser
Coding: c.1963C>T
MANE Select: NM_012309
dbSNP: rs2497976364
Type: single nucleotide variant
Location: chr11:70659926 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.58 · 2 PDB

Full SHANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SHANK2 c.2439+1G>A Pathogenic/Likely pathogenic ★★ same type
SHANK2 p.Arg185Ter Pathogenic ★★ same type
SHANK2 p.Arg642Ter Pathogenic ★★ same type
SHANK2 p.Arg841Ter Pathogenic ★★ same type
SHANK2 p.Gln663Ter Likely pathogenic ★★ same type
SHANK2 p.Glu252Ter Likely pathogenic ★★ same type
SHANK2 p.Ala1729Thr Uncertain significance ★★ ⚠ same type
SHANK2 p.Arg1089His Uncertain significance ★★ 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/shank2-p-pro655ser (accessed [today's date]).

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