Is PGAP1 p.Thr220Met (c.659C>T) pathogenic?

PGAP1 p.Thr220Met (c.659C>T) is classified Conflicting classifications of pathogenicity in PGAP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-01-19). AlphaMissense: likely benign (0.0587); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with PGAP1 p.Thr220Met (c.659C>T)?

PGAP1 p.Thr220Met (c.659C>T) is associated with Inborn genetic diseases, intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Thr220Met (c.659C>T) in the general population?

PGAP1 p.Thr220Met (c.659C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about PGAP1 p.Thr220Met (c.659C>T)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

PGAP1 p.Thr220Met

c.659C>T · rs774987863 · VCV624167

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -8.88	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 3.7	GERP 0.56, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 85 kb · p 0.0064 · regional, not allelic
Overall
CADD	19.34	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 0.0167% Middle Eastern · 1/6,006 alleles

Filtering AF 0.00874% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.00488% 78/1,599,134 alleles · ultra-rare exomes 71/1,446,986 · genomes 7/152,148 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,006
East Asian	0.0157%	6,387
South Asian	0.0148%	6,755
Admixed American	0.00698%	14,320
Remaining individualsnot grpmax-eligible	0.00646%	15,490
European (non-Finnish)	0.00409%	24,441
African / African-American	0.00135%	74,274

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.Thr220Met
Coding: c.659C>T
MANE Select: NM_024989
dbSNP: rs774987863
Type: single nucleotide variant
Location: chr2:196902733 (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

Also linked: intellectual disability, autosomal recessive 42

Similar variants

PGAP1 p.Thr220Arg Uncertain significance ★ ⚠ same residue
PGAP1 p.Gln466Ter Pathogenic ★★ same condition
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Tyr758Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala864Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg231Gln 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-thr220met (accessed [today's date]).

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