Is SHARPIN p.Gly262Ser (c.784G>A) pathogenic?

SHARPIN p.Gly262Ser (c.784G>A) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: ambiguous (0.3918); Very rare (popmax 0.0055%, sas).

How common is SHARPIN p.Gly262Ser (c.784G>A) in the general population?

SHARPIN p.Gly262Ser (c.784G>A) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about SHARPIN p.Gly262Ser (c.784G>A)?

AlphaMissense predicts ambiguous (score 0.3918) — an in-silico prediction, not a clinical call.

SHARPIN p.Gly262Ser

c.784G>A · VCV3441256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Computational evidence

Protein change
AlphaMissense	0.3918	ambiguous
REVEL	0.35	indeterminate
SaProt	LLR -10.97	damaging
Splicing
SpliceAI	Δ0.33	acceptor loss, 13 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.0055% South Asian · 5/90,836 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00186% 30/1,612,034 alleles · very rare exomes 30/1,459,710 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,167
European (non-Finnish)	0.00204%	49,121
Remaining individualsnot grpmax-eligible	0.0016%	62,426

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: SHARPIN
Protein: p.Gly262Ser
Coding: c.784G>A
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099415 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 262: 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-gly262ser (accessed [today's date]).

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