Is SHANK3 p.Pro981= (c.2943T>A) pathogenic?

SHANK3 p.Pro981= (c.2943T>A) is classified Likely benign in SHANK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-06). Ultra-rare (popmax 0.0163%, nfe).

How common is SHANK3 p.Pro981= (c.2943T>A) in the general population?

SHANK3 p.Pro981= (c.2943T>A) is ultra-rare (popmax 0.0163%, nfe) (gnomAD).

SHANK3 p.Pro981=

c.2943T>A · rs1000823234 · VCV1217169

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, nfe)

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 -3.8	GERP -2.7
Overall
CADD	1.639	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0163% European (non-Finnish) · 146/897,058 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.0145% 160/1,100,692 alleles · ultra-rare exomes 152/959,578 · genomes 8/141,114 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0228%	4,389
European (non-Finnish)grpmax	0.0163%	6,144
Admixed American	0.0105%	9,484
Ashkenazi Jewishnot grpmax-eligible	0.00787%	12,702
South Asian	0.00473%	21,157
African / African-American	0.00179%	55,772

Remaining individuals 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.Pro981=
Coding: c.2943T>A
MANE Select: NM_001372044
dbSNP: rs1000823234
Type: single nucleotide variant
Location: chr22:50720551 (GRCh38)
Gene constraint: LOEUF 0.446 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.36 · 3 PDB
Residue 981: the 'disordered' region

Full SHANK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SHANK3 c.2455+1G>A Pathogenic ★★ same type
SHANK3 c.2455+1G>C Pathogenic/Likely pathogenic ★★ same type
SHANK3 c.2838C>G Pathogenic ★★ same type
SHANK3 p.Arg166Ter Pathogenic/Likely pathogenic ★★ same type
SHANK3 p.Arg1733Ter Pathogenic/Likely pathogenic ★★ same type
SHANK3 p.Arg432Ter Pathogenic ★★ same type
SHANK3 p.Asp1564Tyr Pathogenic ★★ same type
SHANK3 p.Gln1364Ter Pathogenic ★★ same type

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-pro981 (accessed [today's date]).

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