Is SHANK2 p.Pro2Leu (c.5C>T) pathogenic?

SHANK2 p.Pro2Leu (c.5C>T) is classified Benign in SHANK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-06-25). Low-frequency (popmax 2.32%, afr); Associated with SHANK2-related disorder.

What condition is associated with SHANK2 p.Pro2Leu (c.5C>T)?

SHANK2 p.Pro2Leu (c.5C>T) is associated with SHANK2-related disorder (ClinVar).

How common is SHANK2 p.Pro2Leu (c.5C>T) in the general population?

SHANK2 p.Pro2Leu (c.5C>T) is low-frequency (popmax 2.32%, afr) (gnomAD).

SHANK2 p.Pro2Leu

c.5C>T · rs115978536 · VCV3057016

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.32%, afr)

Conditions

SHANK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.165	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 0.93, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 486 kb · p 0.00016 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.32% African / African-American · 1,695/73,110 alleles

Filtering AF 2.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.19%

Overall 0.121% 1,879/1,547,256 alleles · low-frequency exomes 878/1,394,922 · genomes 1,001/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.32%	43
Remaining individualsnot grpmax-eligible	0.127%	788
Admixed American	0.124%	808
Middle Eastern	0.0837%	1,195
South Asian	0.00596%	16,781
European (non-Finnish)	0.00306%	32,689

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_012309
dbSNP: rs115978536
Type: single nucleotide variant
Location: chr11:71147322 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.58 · 2 PDB
Residue 2: the 'disordered' region

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

Disease context

SHANK2-related disorder

Similar variants

SHANK2 p.Pro2= Likely benign ★ same residue
SHANK2 p.Gln127Ter Likely pathogenic ★ same condition
SHANK2 p.Gln799Ter Likely pathogenic ★ same condition
SHANK2 p.Arg1636Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
SHANK2 p.Arg766Trp Uncertain significance ★ same condition
SHANK2 p.Arg864Trp Uncertain significance ★ same condition
SHANK2 p.Gly570Ser Uncertain significance ★ same condition
SHANK2 p.Ser1742Ile 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-pro2leu (accessed [today's date]).

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