Is PGAP1 p.Lys166Glu (c.496A>G) pathogenic?

PGAP1 p.Lys166Glu (c.496A>G) is classified Uncertain significance in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.0786); Ultra-rare (popmax 0.0649%, eas); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Lys166Glu (c.496A>G)?

PGAP1 p.Lys166Glu (c.496A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PGAP1 p.Lys166Glu (c.496A>G) in the general population?

PGAP1 p.Lys166Glu (c.496A>G) is ultra-rare (popmax 0.0649%, eas) (gnomAD).

What do computational predictors say about PGAP1 p.Lys166Glu (c.496A>G)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

PGAP1 p.Lys166Glu

c.496A>G · rs768236583 · VCV3211642

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0649%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.78, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	18.47	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 0.0649% East Asian · 29/44,692 alleles

Filtering AF 0.0463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.00205% 33/1,608,710 alleles · ultra-rare exomes 33/1,456,410 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0649%	1,541
Remaining individualsnot grpmax-eligible	0.00482%	20,749
Admixed American	0.00169%	59,202

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.Lys166Glu
Coding: c.496A>G
MANE Select: NM_024989
dbSNP: rs768236583
Type: single nucleotide variant
Location: chr2:196913035 (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.Lys166Arg 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-lys166glu (accessed [today's date]).

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