SHANK2 p.Pro44Leu
c.131C>T · rs554208670 · VCV397532
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0262%, sas)
Conditions
2
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.257 | benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 9 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.16 | unconstrained · MANE · 486 kb · p 0.00016 · regional, not allelic |
| Overall | ||
| CADD | 23.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0262%
South Asian · 22/84,044 alleles
Filtering AF
0.0177%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0149%
Overall
0.00245%
38/1,550,800 alleles · ultra-rare
exomes 31/1,398,492 · genomes 7/152,308 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0262% | 3,820 |
| Middle Eastern | 0.0168% | 5,956 |
| African / African-American | 0.00683% | 14,634 |
| Admixed American | 0.00196% | 51,010 |
| Finnishnot grpmax-eligible | 0.00169% | 59,066 |
| Remaining individualsnot grpmax-eligible | 0.00166% | 60,116 |
| European (non-Finnish) | 0.00061% | 163,852 |
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.Pro44Leu
- Coding
- c.131C>T
- MANE Select
- NM_012309
- dbSNP
- rs554208670
- Type
- single nucleotide variant
- Location
- chr11:71147196 (GRCh38)
- Gene constraint
- LOEUF 0.417 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.58 · 2 PDB
Similar variants
- SHANK2 p.Pro44= Likely benign ★ same residue
- SHANK2 c.2439+1G>A Pathogenic/Likely pathogenic ★★ same condition
- 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.Ser884Phe Uncertain significance ★★ same condition
- SHANK2 p.Arg111His Likely benign ★★ 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-pro44leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown