Is SHARPIN p.Pro294Ser (c.880C>T) pathogenic?

SHARPIN p.Pro294Ser (c.880C>T) is classified Benign in SHARPIN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-29). AlphaMissense: likely benign (0.1092); Common (popmax 5.02%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about SHARPIN p.Pro294Ser (c.880C>T)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

SHARPIN p.Pro294Ser

Q: How common is SHARPIN p.Pro294Ser (c.880C>T) in the general population?

SHARPIN p.Pro294Ser (c.880C>T) is common (popmax 5.02%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.880C>T · rs34674752 · VCV403432

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.02%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.43	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 6.5	GERP 0.73, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	23.1	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 5.02% European (non-Finnish) · 59,241/1,180,000 alleles

Filtering AF 4.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.97%

Overall 4.21% 67,937/1,614,110 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	5.02%	20
Ashkenazi Jewishnot grpmax-eligible	4.75%	21
Remaining individualsnot grpmax-eligible	3.88%	26
Finnishnot grpmax-eligible	3.8%	26
Admixed American	2.41%	42
Middle Eastern	1.62%	62
African / African-American	0.749%	134
South Asian	0.352%	284
Amishnot grpmax-eligible	0.11%	910
East Asian	0.00668%	14,962

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.Pro294Ser
Coding: c.880C>T
MANE Select: NM_030974
dbSNP: rs34674752
Type: single nucleotide variant
Location: chr8:144099319 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 294: a UniProt-annotated variant site (in); 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.Arg365His Benign/Likely 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-pro294ser (accessed [today's date]).

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