Is SHARPIN p.Ala231= (c.693C>T) pathogenic?

SHARPIN p.Ala231= (c.693C>T) is classified Likely benign in SHARPIN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). Very rare (popmax 0.004%, afr).

How common is SHARPIN p.Ala231= (c.693C>T) in the general population?

SHARPIN p.Ala231= (c.693C>T) is very rare (popmax 0.004%, afr) (gnomAD).

SHARPIN p.Ala231=

c.693C>T · rs761738333 · VCV3161561

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -2
Overall
CADD	4.912	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,034 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000929% 15/1,614,056 alleles · very rare exomes 9/1,461,742 · genomes 6/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,011
Admixed American	0.00167%	60,020
South Asian	0.0011%	91,078
European (non-Finnish)	0.000847%	118,000

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.Ala231=
Coding: c.693C>T
MANE Select: NM_030974
dbSNP: rs761738333
Type: single nucleotide variant
Location: chr8:144099585 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 3 PDB
Residue 231: the ubiquitin-like domain; the 'interaction with shank1' region

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

Similar variants

SHARPIN p.Ala231Thr 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.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-ala231 (accessed [today's date]).

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