Is SHARPIN p.Val267Met (c.799G>A) pathogenic?

SHARPIN p.Val267Met (c.799G>A) is classified Uncertain significance in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.3585); Ultra-rare (popmax 0.0231%, sas).

How common is SHARPIN p.Val267Met (c.799G>A) in the general population?

SHARPIN p.Val267Met (c.799G>A) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about SHARPIN p.Val267Met (c.799G>A)?

AlphaMissense predicts ambiguous (score 0.3585) — an in-silico prediction, not a clinical call.

SHARPIN p.Val267Met

c.799G>A · VCV4583380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Computational evidence

Protein change
AlphaMissense	0.3585	ambiguous
REVEL	0.349	indeterminate
SaProt	LLR -3.96	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 0.72, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,872 bp · p 0.12 · regional, not allelic
Overall
CADD	26.3	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 0.0231% South Asian · 21/90,976 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00273% 44/1,612,858 alleles · ultra-rare exomes 39/1,460,660 · genomes 5/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,332
Middle Eastern	0.0165%	6,078
Admixed American	0.00501%	19,969
East Asian	0.00223%	44,902
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.00136%	73,713
African / African-American	0.00133%	74,918

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.Val267Met
Coding: c.799G>A
MANE Select: NM_030974
Type: single nucleotide variant
Location: chr8:144099400 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 267: the ubiquitin-like domain; an α-helix; 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.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

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-val267met (accessed [today's date]).

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