Is SHARPIN p.Arg269Cys (c.805C>T) pathogenic?

SHARPIN p.Arg269Cys (c.805C>T) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). AlphaMissense: likely benign (0.1873); Very rare (popmax 0.00186%, nfe).

How common is SHARPIN p.Arg269Cys (c.805C>T) in the general population?

SHARPIN p.Arg269Cys (c.805C>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about SHARPIN p.Arg269Cys (c.805C>T)?

AlphaMissense predicts likely benign (score 0.1873) — an in-silico prediction, not a clinical call.

SHARPIN p.Arg269Cys

c.805C>T · VCV3318221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1873	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -10.81	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.73, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	25.4	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 0.00186% European (non-Finnish) · 22/1,179,696 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00161% 26/1,613,354 alleles · very rare exomes 25/1,461,148 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,622
Admixed American	0.00167%	59,954
Remaining individualsnot grpmax-eligible	0.0016%	62,450
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,040

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.Arg269Cys
Coding: c.805C>T
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099394 (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.Arg269His 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-arg269cys (accessed [today's date]).

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