Is PGAP2 p.Arg18Cys (c.52C>T) pathogenic?

PGAP2 p.Arg18Cys (c.52C>T) is classified Conflicting classifications of pathogenicity in PGAP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.3722); Rare (popmax 0.185%, eas).

How common is PGAP2 p.Arg18Cys (c.52C>T) in the general population?

PGAP2 p.Arg18Cys (c.52C>T) is rare (popmax 0.185%, eas) (gnomAD).

What do computational predictors say about PGAP2 p.Arg18Cys (c.52C>T)?

AlphaMissense predicts ambiguous (score 0.3722) — an in-silico prediction, not a clinical call.

PGAP2 p.Arg18Cys

c.52C>T · rs200164387 · VCV738390

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3722 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3722	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 161 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.185% East Asian · 83/44,890 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.141%

Overall 0.0131% 211/1,614,068 alleles · rare exomes 191/1,461,802 · genomes 20/152,266 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.185%	541
Remaining individualsnot grpmax-eligible	0.032%	3,125
South Asian	0.0285%	3,503
Middle Eastern	0.0165%	6,058
African / African-American	0.00666%	15,004
European (non-Finnish)	0.00644%	15,526

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: PGAP2
Protein: p.Arg18Cys
Coding: c.52C>T
MANE Select: NM_014489
dbSNP: rs200164387
Type: single nucleotide variant
Location: chr11:3811311 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00

Full PGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGAP2 p.Arg18His Uncertain significance ★ ⚠ same residue
PGAP2 p.Ala127Val Likely pathogenic ★★ same type
PGAP2 p.Arg238Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
PGAP2 p.Thr294Met Likely pathogenic ★★ same type
PGAP2 c.602-3C>T Uncertain significance ★★ same type
PGAP2 p.Ala187Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Ala33Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Arg238Cys 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/pgap2-p-arg18cys (accessed [today's date]).

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