Is PPCS p.Pro168Thr (c.502C>A) pathogenic?

PPCS p.Pro168Thr (c.502C>A) is classified Uncertain significance in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.0899); Very rare (popmax 0.00134%, afr).

How common is PPCS p.Pro168Thr (c.502C>A) in the general population?

PPCS p.Pro168Thr (c.502C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PPCS p.Pro168Thr (c.502C>A)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

PPCS p.Pro168Thr

c.502C>A · rs1221298323 · VCV2872105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 687 bp · p 0.55 · regional, not allelic
Overall
CADD	20.9	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 0.00134% African / African-American · 1/74,736 alleles

Overall 6.27e-05% 1/1,594,250 alleles · very rare exomes 0/1,442,030 · genomes 1/152,220 · 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: PPCS
Protein: p.Pro168Thr
Coding: c.502C>A
MANE Select: NM_024664
dbSNP: rs1221298323
Type: single nucleotide variant
Location: chr1:42457067 (GRCh38)

Full PPCS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/ppcs-p-pro168thr (accessed [today's date]).

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