Is SHARPIN p.Gly217Asp (c.650G>A) pathogenic?

SHARPIN p.Gly217Asp (c.650G>A) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.5251); Absent from gnomAD v4.1.

How common is SHARPIN p.Gly217Asp (c.650G>A) in the general population?

SHARPIN p.Gly217Asp (c.650G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SHARPIN p.Gly217Asp (c.650G>A)?

AlphaMissense predicts ambiguous (score 0.5251) — an in-silico prediction, not a clinical call.

SHARPIN p.Gly217Asp

c.650G>A · VCV4164552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5251 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5251	ambiguous
REVEL	0.176	moderately benign-leaning
SaProt	LLR -13.08	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SHARPIN
Protein: p.Gly217Asp
Coding: c.650G>A
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099712 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 217: the 'interaction with shank1' region

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

Similar variants

SHARPIN p.Arg365His Benign/Likely benign ★★ same type
SHARPIN p.Pro294Ser Benign ★★ same type
SHARPIN p.Ala184Pro Uncertain significance ★ ⚠ same type
SHARPIN p.Ala184Thr Uncertain significance ★ ⚠ same type
SHARPIN p.Ala212Asp Uncertain significance ★ ⚠ same type
SHARPIN p.Ala231Thr Uncertain significance ★ ⚠ same type
SHARPIN p.Ala235Val Uncertain significance ★ ⚠ same type
SHARPIN p.Ala295Gly Uncertain significance ★ ⚠ 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/sharpin-p-gly217asp (accessed [today's date]).

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