Is SHARPIN p.Arg269His (c.806G>A) pathogenic?

SHARPIN p.Arg269His (c.806G>A) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-14). AlphaMissense: likely benign (0.1536); Very rare (popmax 0.00933%, afr).

How common is SHARPIN p.Arg269His (c.806G>A) in the general population?

SHARPIN p.Arg269His (c.806G>A) is very rare (popmax 0.00933%, afr) (gnomAD).

What do computational predictors say about SHARPIN p.Arg269His (c.806G>A)?

AlphaMissense predicts likely benign (score 0.1536) — an in-silico prediction, not a clinical call.

SHARPIN p.Arg269His

c.806G>A · rs200777435 · VCV2335018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1536	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.72, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	23.8	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 0.00933% African / African-American · 7/75,026 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00192% 31/1,613,240 alleles · very rare exomes 23/1,460,928 · genomes 8/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,718
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.00178%	56,170
South Asian	0.0011%	91,008

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.Arg269His
Coding: c.806G>A
MANE Select: NM_030974
dbSNP: rs200777435
Type: single nucleotide variant
Location: chr8:144099393 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 269: the ubiquitin-like domain; a β-strand; the 'interaction with shank1' region

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

Similar variants

SHARPIN p.Arg269Cys Uncertain significance ★ ⚠ same residue
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

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-arg269his (accessed [today's date]).

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