Is APTX c.483+91C>T pathogenic?

APTX c.483+91C>T is classified Benign in APTX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-31). Common (popmax 26.7%, mid) — too common for a highly-penetrant pathogenic allele.

APTX c.483+91C>T

Q: How common is APTX c.483+91C>T in the general population?

APTX c.483+91C>T is common (popmax 26.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs884546 · VCV1290675

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 26.7%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +91	deep intronic (+91 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -3.4
Non-coding constraint	Z 1.24	1 kb window · o/e 0.91 · regional · uncalibrated
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 26.7% Middle Eastern · 1,572/5,898 alleles

Filtering AF 25.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.1%

Overall 21% 317,729/1,511,114 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	29.9%	3
Ashkenazi Jewishnot grpmax-eligible	28.8%	3
Middle Easterngrpmax	26.7%	4
European (non-Finnish)	22.9%	4
Finnishnot grpmax-eligible	22.2%	4
Remaining individualsnot grpmax-eligible	20.7%	5
Admixed American	18.3%	5
African / African-American	14.5%	7
South Asian	10.1%	10
East Asian	4.3%	23

Amish 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: APTX
Coding: c.483+91C>T
MANE Select: NM_001195248
dbSNP: rs884546
Type: single nucleotide variant
Location: chr9:32987453 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB

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

Similar variants

APTX c.875-2A>G Pathogenic/Likely pathogenic ★★ same type
APTX p.Ala198Val Likely pathogenic ★★ same type
APTX p.Arg16Ter Pathogenic/Likely pathogenic ★★ same type
APTX p.Arg247Ter Pathogenic/Likely pathogenic ★★ same type
APTX p.Gln130Ter Pathogenic/Likely pathogenic ★★ same type
APTX p.Gln187Ter Pathogenic ★★ same type
APTX p.Trp279Arg Pathogenic/Likely pathogenic ★★ same type
APTX p.Trp279Ter Pathogenic ★★ 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/aptx-c-483-plus-91c-t (accessed [today's date]).

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