Is PGAP3 p.Arg248Trp (c.742C>T) pathogenic?

PGAP3 p.Arg248Trp (c.742C>T) is classified Uncertain significance in PGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely benign (0.0918); Ultra-rare (popmax 0.0115%, amr).

How common is PGAP3 p.Arg248Trp (c.742C>T) in the general population?

PGAP3 p.Arg248Trp (c.742C>T) is ultra-rare (popmax 0.0115%, amr) (gnomAD).

What do computational predictors say about PGAP3 p.Arg248Trp (c.742C>T)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

PGAP3 p.Arg248Trp

c.742C>T · rs766144739 · VCV1380168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -9.37	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 5.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	28.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0115% Admixed American · 6/52,274 alleles

Filtering AF 0.00491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0034%

Overall 0.000829% 13/1,568,780 alleles · ultra-rare exomes 11/1,416,620 · genomes 2/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0115%	8,712
Remaining individualsnot grpmax-eligible	0.00164%	60,826
African / African-American	0.00135%	73,912
European (non-Finnish)	0.000432%	231,467

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: PGAP3
Protein: p.Arg248Trp
Coding: c.742C>T
MANE Select: NM_033419
dbSNP: rs766144739
Type: single nucleotide variant
Location: chr17:39673208 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17

Full PGAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGAP3 p.Arg248Gln Likely benign ★★ same residue
PGAP3 p.Arg248= Likely benign ★ same residue
PGAP3 c.558-10G>A Pathogenic/Likely pathogenic ★★ same type
PGAP3 c.694+1G>A Pathogenic ★★ same type
PGAP3 p.Asp305Gly Pathogenic/Likely pathogenic ★★ same type
PGAP3 p.Gln89Ter Pathogenic ★★ same type
PGAP3 p.Glu37Ter Pathogenic ★★ same type
PGAP3 p.His284Arg Pathogenic/Likely pathogenic ★★ ⚠ 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/pgap3-p-arg248trp (accessed [today's date]).

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