Is PGAP1 p.Pro680= (c.2040C>T) pathogenic?

PGAP1 p.Pro680= (c.2040C>T) is classified Likely benign in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-03). Ultra-rare (popmax 0.0117%, amr); Associated with intellectual disability, autosomal recessive 42.

What condition is associated with PGAP1 p.Pro680= (c.2040C>T)?

PGAP1 p.Pro680= (c.2040C>T) is associated with intellectual disability, autosomal recessive 42 (ClinVar).

How common is PGAP1 p.Pro680= (c.2040C>T) in the general population?

PGAP1 p.Pro680= (c.2040C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

PGAP1 p.Pro680=

c.2040C>T · rs772471528 · VCV2699772

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

intellectual disability, autosomal recessive 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -0.13, phastCons 0.88
Overall
CADD	6.513	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,004 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000496% 8/1,613,284 alleles · ultra-rare exomes 8/1,461,078 · genomes 0/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,572
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Pro680=
Coding: c.2040C>T
MANE Select: NM_024989
dbSNP: rs772471528
Type: single nucleotide variant
Location: chr2:196847113 (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

intellectual disability, autosomal recessive 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PGAP1 p.Pro680Arg 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.Arg231Gln Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg250His 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-pro680 (accessed [today's date]).

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