Is SHANK3 p.Pro756= (c.2268C>G) pathogenic?

SHANK3 p.Pro756= (c.2268C>G) is classified Benign in SHANK3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.88%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SHANK3 p.Pro756= (c.2268C>G)?

SHANK3 p.Pro756= (c.2268C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SHANK3 p.Pro756= (c.2268C>G) in the general population?

SHANK3 p.Pro756= (c.2268C>G) is rare (popmax 0.88%, nfe) (gnomAD).

SHANK3 p.Pro756=

c.2268C>G · rs61731160 · VCV588392

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.88%, 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 -1.4	GERP -4.5
Overall
CADD	4.741	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.88% European (non-Finnish) · 10,109/1,148,554 alleles

Filtering AF 0.866% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.86%

Overall 0.783% 12,167/1,553,958 alleles · rare exomes 11,403/1,401,758 · genomes 764/152,200 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.97%	51
European (non-Finnish)grpmax	0.88%	114
South Asian	0.858%	117
Remaining individualsnot grpmax-eligible	0.769%	130
Admixed American	0.234%	427
Middle Eastern	0.201%	497
Finnishnot grpmax-eligible	0.165%	607
African / African-American	0.104%	964
East Asian	0.00243%	41,092

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro756=
Coding: c.2268C>G
MANE Select: NM_001372044
dbSNP: rs61731160
Type: single nucleotide variant
Location: chr22:50706085 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.36 · 3 PDB
Residue 756: the 'disordered' region; the 'required for interaction with abi1' region

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-pro756 (accessed [today's date]).

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