Is SHARPIN p.His245Arg (c.734A>G) pathogenic?

SHARPIN p.His245Arg (c.734A>G) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.1745); Ultra-rare (popmax 0.0134%, afr).

How common is SHARPIN p.His245Arg (c.734A>G) in the general population?

SHARPIN p.His245Arg (c.734A>G) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about SHARPIN p.His245Arg (c.734A>G)?

AlphaMissense predicts likely benign (score 0.1745) — an in-silico prediction, not a clinical call.

SHARPIN p.His245Arg

c.734A>G · rs369335155 · VCV2523106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1745	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -4.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.42	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% African / African-American · 10/74,860 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.0013% 21/1,613,744 alleles · ultra-rare exomes 9/1,461,724 · genomes 12/152,020 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,486
Admixed American	0.0133%	7,498
European (non-Finnish)	0.000254%	393,323

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.His245Arg
Coding: c.734A>G
MANE Select: NM_030974
dbSNP: rs369335155
Type: single nucleotide variant
Location: chr8:144099544 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 245: 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-his245arg (accessed [today's date]).

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