Is PGAP3 p.Ser153Pro (c.457T>C) pathogenic?

PGAP3 p.Ser153Pro (c.457T>C) is classified Uncertain significance in PGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-01). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 0.000436%, nfe).

How common is PGAP3 p.Ser153Pro (c.457T>C) in the general population?

PGAP3 p.Ser153Pro (c.457T>C) is very rare (popmax 0.000436%, nfe) (gnomAD).

What do computational predictors say about PGAP3 p.Ser153Pro (c.457T>C)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

PGAP3 p.Ser153Pro

c.457T>C · rs2057352977 · VCV872719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000436%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic · top 1% in PGAP3
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000436% European (non-Finnish) · 5/1,146,666 alleles

Filtering AF 0.000128% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000322% 5/1,551,232 alleles · very rare exomes 5/1,399,002 · genomes 0/152,230 · joint denominator

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.Ser153Pro
Coding: c.457T>C
MANE Select: NM_033419
dbSNP: rs2057352977
Type: single nucleotide variant
Location: chr17:39674655 (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 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
PGAP3 p.His284Tyr Pathogenic/Likely pathogenic ★★ same type
PGAP3 p.Pro105Gln 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-ser153pro (accessed [today's date]).

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