Is SHANK3 p.Pro845= (c.2535G>A) pathogenic?

SHANK3 p.Pro845= (c.2535G>A) is classified Benign in SHANK3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-01). Rare (popmax 0.615%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SHANK3 p.Pro845= (c.2535G>A)?

SHANK3 p.Pro845= (c.2535G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SHANK3 p.Pro845= (c.2535G>A) in the general population?

SHANK3 p.Pro845= (c.2535G>A) is rare (popmax 0.615%, nfe) (gnomAD).

SHANK3 p.Pro845=

c.2535G>A · rs117066889 · VCV589141

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.615%, 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 -2.8	GERP -3
Overall
CADD	2.168	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.615% European (non-Finnish) · 7,251/1,179,064 alleles

Filtering AF 0.603% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.598%

Overall 0.596% 9,614/1,612,438 alleles · rare exomes 8,777/1,460,164 · genomes 837/152,274 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.91%	34
European (non-Finnish)grpmax	0.615%	163
Remaining individualsnot grpmax-eligible	0.426%	235
Admixed American	0.159%	630
African / African-American	0.0787%	1,271
South Asian	0.0749%	1,336
Middle Eastern	0.0496%	2,018
Ashkenazi Jewishnot grpmax-eligible	0.0305%	3,284
East Asian	0.00447%	22,372

Finnish 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.Pro845=
Coding: c.2535G>A
MANE Select: NM_001372044
dbSNP: rs117066889
Type: single nucleotide variant
Location: chr22:50715713 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.36 · 3 PDB
Residue 845: the 'disordered' 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-pro845 (accessed [today's date]).

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