Is SHARPIN p.Arg365His (c.1094G>A) pathogenic?

SHARPIN p.Arg365His (c.1094G>A) is classified Benign/Likely benign in SHARPIN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: ambiguous (0.3804); Low-frequency (popmax 2.8%, sas).

How common is SHARPIN p.Arg365His (c.1094G>A) in the general population?

SHARPIN p.Arg365His (c.1094G>A) is low-frequency (popmax 2.8%, sas) (gnomAD).

What do computational predictors say about SHARPIN p.Arg365His (c.1094G>A)?

AlphaMissense predicts ambiguous (score 0.3804) — an in-silico prediction, not a clinical call.

SHARPIN p.Arg365His

c.1094G>A · rs112552278 · VCV710592

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3804 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.8%, sas)

Computational evidence

Protein change
AlphaMissense	0.3804	ambiguous
REVEL	0.454	indeterminate
SaProt	LLR -7.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.72, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	28.8	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 2.8% South Asian · 2,451/87,466 alleles

Filtering AF 2.71% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.67%

Overall 0.565% 8,994/1,592,062 alleles · low-frequency exomes 8,254/1,439,812 · genomes 740/152,250 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.8%	36
Amishnot grpmax-eligible	2.19%	46
Ashkenazi Jewishnot grpmax-eligible	1.69%	59
Middle Eastern	1.1%	91
Remaining individualsnot grpmax-eligible	0.704%	142
Finnishnot grpmax-eligible	0.687%	145
European (non-Finnish)	0.417%	240
Admixed American	0.301%	332
African / African-American	0.0709%	1,411
East Asian	0.0179%	5,584

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.Arg365His
Coding: c.1094G>A
MANE Select: NM_030974
dbSNP: rs112552278
Type: single nucleotide variant
Location: chr8:144098948 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB

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

Similar variants

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
SHARPIN p.Ala306Ser 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-arg365his (accessed [today's date]).

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