Is PGAP1 p.Arg447His (c.1340G>A) pathogenic?

PGAP1 p.Arg447His (c.1340G>A) is classified Likely benign in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely benign (0.0627); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Arg447His (c.1340G>A)?

PGAP1 p.Arg447His (c.1340G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP1 p.Arg447His (c.1340G>A) in the general population?

PGAP1 p.Arg447His (c.1340G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about PGAP1 p.Arg447His (c.1340G>A)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

PGAP1 p.Arg447His

c.1340G>A · rs773874771 · VCV2589809

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 0.64, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	18.71	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 0.0166% Middle Eastern · 1/6,022 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.00349% 56/1,603,072 alleles · ultra-rare exomes 50/1,451,304 · genomes 6/151,768 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,022
East Asian	0.0112%	8,902
Finnishnot grpmax-eligible	0.00627%	15,941
African / African-American	0.00537%	18,606
South Asian	0.00332%	30,108
European (non-Finnish)	0.00324%	30,844
Remaining individualsnot grpmax-eligible	0.00161%	62,096

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.Arg447His
Coding: c.1340G>A
MANE Select: NM_024989
dbSNP: rs773874771
Type: single nucleotide variant
Location: chr2:196880086 (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

Disease context

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

Similar variants

PGAP1 p.Arg447Cys Uncertain significance ★ ⚠ same residue
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala864Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg803His Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg814Cys Uncertain significance ★★ ⚠ same condition
PGAP1 p.Asn129Ser Uncertain significance ★★ ⚠ same condition
PGAP1 p.Asn363Asp Uncertain significance ★★ ⚠ 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/pgap1-p-arg447his (accessed [today's date]).

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