Is GPAA1 p.Val232fs (c.694dup) pathogenic?

GPAA1 p.Val232fs (c.694dup) is classified Pathogenic in GPAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-09). Ultra-rare (popmax 0.0165%, mid).

How common is GPAA1 p.Val232fs (c.694dup) in the general population?

GPAA1 p.Val232fs (c.694dup) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

GPAA1 p.Val232fs

c.694dup · rs782232273 · VCV2084338

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 6 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Overall
CADD	34.0	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00124% 20/1,612,920 alleles · ultra-rare exomes 17/1,461,348 · genomes 3/151,572 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,114
Middle Easterngrpmax	0.0165%	6,078
Admixed American	0.00333%	29,986
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.00017%	589,929

Ashkenazi Jewish 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: GPAA1
Protein: p.Val232fs
Coding: c.694dup
MANE Select: NM_003801
dbSNP: rs782232273
Type: Duplication
Location: chr8:144084209 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 232: a β-strand

Full GPAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPAA1 c.1010+22dup Benign ★ same type
GPAA1 c.1164+7dup Likely benign ★ same type
GPAA1 c.1260+14dup Benign ★ same type
GPAA1 c.616+16dup Likely benign ★ same type
GPAA1 c.813+4_813+11dup Likely benign ★ same type
GPAA1 c.814-5dup 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/gpaa1-p-val232fs (accessed [today's date]).

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