Is SHANK2 p.Arg595His (c.1784G>A) pathogenic?

SHANK2 p.Arg595His (c.1784G>A) is classified Uncertain significance in SHANK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-09). AlphaMissense: ambiguous (0.4944); Ultra-rare (popmax 0.0229%, mid); Associated with SHANK2-related disorder.

What condition is associated with SHANK2 p.Arg595His (c.1784G>A)?

SHANK2 p.Arg595His (c.1784G>A) is associated with SHANK2-related disorder (ClinVar).

How common is SHANK2 p.Arg595His (c.1784G>A) in the general population?

SHANK2 p.Arg595His (c.1784G>A) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about SHANK2 p.Arg595His (c.1784G>A)?

AlphaMissense predicts ambiguous (score 0.4944) — an in-silico prediction, not a clinical call.

SHANK2 p.Arg595His

c.1784G>A · VCV3357200

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4944 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Conditions

SHANK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.4944	ambiguous
REVEL	0.269	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 486 kb · p 0.00016 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R216H vs ClinVar R595H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% Middle Eastern · 1/4,370 alleles

Filtering AF 0.00407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00342%

Overall 0.00501% 36/718,612 alleles · ultra-rare exomes 25/566,304 · genomes 11/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,370
East Asian	0.0107%	9,323
Remaining individualsnot grpmax-eligible	0.00609%	16,410
Admixed American	0.006%	16,675
European (non-Finnish)	0.00597%	16,743
Ashkenazi Jewishnot grpmax-eligible	0.00425%	23,502
African / African-American	0.00174%	57,380
South Asian	0.00148%	67,598

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.Arg595His
Coding: c.1784G>A
MANE Select: NM_012309
Type: single nucleotide variant
Location: chr11:70698757 (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

SHANK2-related disorder

Similar variants

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
SHANK2 p.Thr1176Met 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-arg595his (accessed [today's date]).

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