Is SHARPIN p.Val288Leu (c.862G>C) pathogenic?

SHARPIN p.Val288Leu (c.862G>C) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.4033); Absent from gnomAD v4.1.

How common is SHARPIN p.Val288Leu (c.862G>C) in the general population?

SHARPIN p.Val288Leu (c.862G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SHARPIN p.Val288Leu (c.862G>C)?

AlphaMissense predicts ambiguous (score 0.4033) — an in-silico prediction, not a clinical call.

SHARPIN p.Val288Leu

c.862G>C · VCV3795546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4033 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4033	ambiguous
REVEL	0.128	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -0.47, phastCons 0.099
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	13.59	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.Val288Leu
Coding: c.862G>C
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099337 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 288: the ubiquitin-like domain; 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-val288leu (accessed [today's date]).

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