Is SQSTM1 p.Pro232= (c.696G>A) pathogenic?

SQSTM1 p.Pro232= (c.696G>A) is classified Likely benign in SQSTM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). Ultra-rare (popmax 0.0213%, afr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 1.

How common is SQSTM1 p.Pro232= (c.696G>A) in the general population?

SQSTM1 p.Pro232= (c.696G>A) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

SQSTM1 p.Pro232=

Q: What condition is associated with SQSTM1 p.Pro232= (c.696G>A)?

SQSTM1 p.Pro232= (c.696G>A) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 1, Paget disease of bone 2, early-onset (ClinVar).

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.696G>A · rs145688323 · VCV1143214

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 1

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 0.57	GERP -1, phastCons 1
Overall
CADD	11.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0213% African / African-American · 16/75,058 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00149% 24/1,614,122 alleles · ultra-rare exomes 15/1,461,778 · genomes 9/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,691
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,508
Finnishnot grpmax-eligible	0.00156%	63,952
European (non-Finnish)	0.000424%	236,008

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: SQSTM1
Protein: p.Pro232=
Coding: c.696G>A
MANE Select: NM_003900
dbSNP: rs145688323
Type: single nucleotide variant
Location: chr5:179825168 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.81 · 26 PDB
Residue 232: the 'disordered' region; a UniProt-annotated variant site (in ftdals3)

Full SQSTM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Paget disease of bone 2, early-onset

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

SQSTM1 p.Pro232Leu Uncertain significance ★ ⚠ same residue
SQSTM1 c.301+1G>T Pathogenic/Likely pathogenic ★★ same condition
SQSTM1 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
SQSTM1 p.Glu389Gln Pathogenic ★★ ⚠ same condition
SQSTM1 p.Met404Val Pathogenic ★★ same condition
SQSTM1 c.1166-5G>A Uncertain significance ★★ same condition
SQSTM1 c.205+14G>T Uncertain significance ★★ same condition
SQSTM1 c.754+5G>A Uncertain significance ★★ same condition

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/sqstm1-p-pro232 (accessed [today's date]).

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