Is SHARPIN p.Asp161Tyr (c.481G>T) pathogenic?

SHARPIN p.Asp161Tyr (c.481G>T) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0926); Very rare (popmax 0.00253%, eas).

How common is SHARPIN p.Asp161Tyr (c.481G>T) in the general population?

SHARPIN p.Asp161Tyr (c.481G>T) is very rare (popmax 0.00253%, eas) (gnomAD).

What do computational predictors say about SHARPIN p.Asp161Tyr (c.481G>T)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

SHARPIN p.Asp161Tyr

c.481G>T · VCV3953963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00253%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -2, phastCons 0.61
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	16.69	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 0.00253% East Asian · 1/39,460 alleles

Filtering AF 0.000519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000379%

Overall 0.000776% 12/1,545,826 alleles · very rare exomes 11/1,401,728 · genomes 1/144,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00253%	39,460
European (non-Finnish)	0.000967%	103,395

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.Asp161Tyr
Coding: c.481G>T
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099965 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 161: the 'self-association' region; the 'disordered' region

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

Similar variants

SHARPIN p.Asp161Glu 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-asp161tyr (accessed [today's date]).

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