Is APTX p.His112fs (c.336_337del) pathogenic?

APTX p.His112fs (c.336337del) is classified Pathogenic in APTX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-03). Very rare (popmax 0.000254%, nfe).

How common is APTX p.His112fs (c.336_337del) in the general population?

APTX p.His112fs (c.336_337del) is very rare (popmax 0.000254%, nfe) (gnomAD).

APTX p.His112fs

c.336_337del · rs1428108985 · VCV2910226

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.38	GERP 0.74, phastCons 0.058
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,048 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,018 alleles · very rare

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
Protein: p.His112fs
Coding: c.336_337del
MANE Select: NM_001195248
dbSNP: rs1428108985
Type: Microsatellite
Location: chr9:32987690 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 112: a β-strand

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

Similar variants

APTX c.484-3_484-2insTTTTTTTTTTTG Conflicting classifications of pathogenicity ★ same type
APTX c.484-3_484-2insTTTTTTTTTTG Likely benign ★ same type
APTX c.484-3_484-2insTTTTTTTTTTTTG Likely benign ★ same type
APTX c.-4-285AAAT[4] Likely benign ★ 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-p-his112fs (accessed [today's date]).

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