Is PGAP2 p.Arg238Cys (c.712C>T) pathogenic?

PGAP2 p.Arg238Cys (c.712C>T) is classified Uncertain significance in PGAP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1191); Ultra-rare (popmax 0.0942%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PGAP2 p.Arg238Cys (c.712C>T)?

PGAP2 p.Arg238Cys (c.712C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP2 p.Arg238Cys (c.712C>T) in the general population?

PGAP2 p.Arg238Cys (c.712C>T) is ultra-rare (popmax 0.0942%, nfe) (gnomAD).

What do computational predictors say about PGAP2 p.Arg238Cys (c.712C>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

PGAP2 p.Arg238Cys

c.712C>T · rs117338939 · VCV377014

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0942%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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 0.88	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R177C vs ClinVar R238C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0942% European (non-Finnish) · 1,111/1,180,000 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0877%

Overall 0.073% 1,179/1,614,126 alleles · ultra-rare exomes 1,103/1,461,834 · genomes 76/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0942%	1,062
Remaining individualsnot grpmax-eligible	0.048%	2,084
African / African-American	0.0293%	3,411
East Asian	0.0245%	4,081
Finnishnot grpmax-eligible	0.00312%	32,018
South Asian	0.0022%	45,538
Admixed American	0.00167%	60,012

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.Arg238Cys
Coding: c.712C>T
MANE Select: NM_014489
dbSNP: rs117338939
Type: single nucleotide variant
Location: chr11:3825023 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00
Residue 177 UniProt numbering: a UniProt-annotated variant site (in hpmrs3; does not affect protein expression; decreases gpi anchor biosynthetic process)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PGAP2 p.Arg238Pro Pathogenic/Likely pathogenic ★★ ⚠ same residue
PGAP2 p.Ala187Thr Uncertain significance ★★ ⚠ same condition
PGAP2 p.Ala33Thr Uncertain significance ★★ ⚠ same condition
PGAP2 p.Glu204Lys Uncertain significance ★★ ⚠ same condition
PGAP2 p.Leu161Phe Uncertain significance ★★ ⚠ same condition
PGAP2 p.Val183Met Uncertain significance ★★ ⚠ same condition
PGAP2 p.Val4Ile Uncertain significance ★★ ⚠ same condition
PGAP2 p.Val182Ile Benign/Likely benign ★★ same condition

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-arg238cys (accessed [today's date]).

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