Is SHANK2 p.Ser884Phe (c.2651C>T) pathogenic?

SHANK2 p.Ser884Phe (c.2651C>T) is classified Uncertain significance in SHANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-02). AlphaMissense: likely pathogenic (0.7541); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SHANK2 p.Ser884Phe (c.2651C>T)?

SHANK2 p.Ser884Phe (c.2651C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SHANK2 p.Ser884Phe (c.2651C>T) in the general population?

SHANK2 p.Ser884Phe (c.2651C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SHANK2 p.Ser884Phe (c.2651C>T)?

AlphaMissense predicts likely pathogenic (score 0.7541) — an in-silico prediction, not a clinical call.

SHANK2 p.Ser884Phe

c.2651C>T · rs2058830670 · VCV2271786

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7541	likely pathogenic
REVEL	0.344	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.53, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 173 kb · p 1.1e-09 · regional, not allelic
Overall
CADD	27.9	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 S505F vs ClinVar S884F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,173,862 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,601,230 alleles · very rare exomes 2/1,449,324 · genomes 0/151,906 · joint denominator

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: SHANK2
Protein: p.Ser884Phe
Coding: c.2651C>T
MANE Select: NM_012309
dbSNP: rs2058830670
Type: single nucleotide variant
Location: chr11:70487642 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHANK2 p.Arg227Cys Uncertain significance ★★ same condition
SHANK2 p.Arg783His Uncertain significance ★★ ⚠ same condition
SHANK2 p.Glu1183Lys Uncertain significance ★★ ⚠ same condition
SHANK2 p.Pro1446Leu Uncertain significance ★★ ⚠ same condition
SHANK2 p.Pro44Leu Uncertain significance ★★ same condition
SHANK2 p.Arg111His Likely benign ★★ same condition
SHANK2 p.Ile1361= Likely benign ★★ same condition
SHANK2 c.745-6T>C 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/shank2-p-ser884phe (accessed [today's date]).

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