Is SHANK2 p.Arg73Pro (c.218G>C) pathogenic?

SHANK2 p.Arg73Pro (c.218G>C) is classified Uncertain significance in SHANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). Very rare (popmax 0.00196%, amr); Associated with Inborn genetic diseases.

What condition is associated with SHANK2 p.Arg73Pro (c.218G>C)?

SHANK2 p.Arg73Pro (c.218G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SHANK2 p.Arg73Pro (c.218G>C) in the general population?

SHANK2 p.Arg73Pro (c.218G>C) is very rare (popmax 0.00196%, amr) (gnomAD).

SHANK2 p.Arg73Pro

c.218G>C · rs1555100977 · VCV2288066

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.465	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 486 kb · p 0.00016 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/51,004 alleles

Filtering AF 0.000128% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000451% 7/1,551,628 alleles · very rare exomes 7/1,399,314 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	51,004
Remaining individualsnot grpmax-eligible	0.00166%	60,122
European (non-Finnish)	0.000436%	229,391

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.Arg73Pro
Coding: c.218G>C
MANE Select: NM_012309
dbSNP: rs1555100977
Type: single nucleotide variant
Location: chr11:71119022 (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.Arg73Gln Uncertain significance ★ same residue
SHANK2 p.Arg73Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
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.Ser884Phe 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-arg73pro (accessed [today's date]).

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