Is PGAP1 p.Arg231Ter (c.691C>T) pathogenic?

PGAP1 p.Arg231Ter (c.691C>T) is classified Pathogenic/Likely pathogenic in PGAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-15). Very rare (popmax 0.00017%, nfe).

How common is PGAP1 p.Arg231Ter (c.691C>T) in the general population?

PGAP1 p.Arg231Ter (c.691C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

PGAP1 p.Arg231Ter

c.691C>T · rs1364192556 · VCV450534

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 27
Splicing
SpliceAI	Δ0.43	acceptor loss · deltas
Pangolin	Δ0.25	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -1, phastCons 0.99
Overall
CADD	36.0	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 0.00017% European (non-Finnish) · 2/1,178,326 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,716 alleles · very rare exomes 2/1,459,676 · genomes 1/152,040 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,990
European (non-Finnish)grpmax	0.00017%	589,164

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: PGAP1
Protein: p.Arg231Ter
Coding: c.691C>T
MANE Select: NM_024989
dbSNP: rs1364192556
Type: single nucleotide variant
Location: chr2:196902701 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 89.15

Full PGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGAP1 p.Arg231Gln Uncertain significance ★★ ⚠ same residue
PGAP1 p.Gln466Ter Pathogenic ★★ same type
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same type
PGAP1 p.Tyr758Ter Pathogenic/Likely pathogenic ★★ same type
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same type
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same type
PGAP1 p.Ala864Val Uncertain significance ★★ ⚠ same type
PGAP1 p.Arg250His 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/pgap1-p-arg231ter (accessed [today's date]).

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