Is APPL1 p.Ser232= (c.696C>T) pathogenic?

APPL1 p.Ser232= (c.696C>T) is classified Likely benign in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). Very rare (popmax 0.00538%, afr).

How common is APPL1 p.Ser232= (c.696C>T) in the general population?

APPL1 p.Ser232= (c.696C>T) is very rare (popmax 0.00538%, afr) (gnomAD).

APPL1 p.Ser232=

c.696C>T · VCV4689480

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00538%, 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 0.71	GERP -2, phastCons 1
Overall
CADD	11.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00538% African / African-American · 4/74,302 alleles

Filtering AF 0.00392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00358%

Overall 0.00521% 83/1,591,810 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0204%	4,907
Remaining individualsnot grpmax-eligible	0.00973%	10,280
African / African-Americangrpmax	0.00538%	18,575
European (non-Finnish)	0.00499%	20,037
East Asian	0.00449%	22,287

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: APPL1
Protein: p.Ser232=
Coding: c.696C>T
MANE Select: NM_012096
Type: single nucleotide variant
Location: chr3:57247469 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 232: the bar domain; an α-helix; the 'required for rab5a binding' region

Full APPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APPL1 c.1658+6T>G Uncertain significance ★★ same type
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type
APPL1 p.Arg412Trp Uncertain significance ★★ ⚠ same type
APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same type
APPL1 p.Arg526His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg633His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg72Cys 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/appl1-p-ser232 (accessed [today's date]).

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