Is PPCS p.Leu74Pro (c.221T>C) pathogenic?

PPCS p.Leu74Pro (c.221T>C) is classified Uncertain significance in PPCS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.8897); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPCS p.Leu74Pro (c.221T>C)?

PPCS p.Leu74Pro (c.221T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PPCS p.Leu74Pro (c.221T>C) in the general population?

PPCS p.Leu74Pro (c.221T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PPCS p.Leu74Pro (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.8897) — an in-silico prediction, not a clinical call.

PPCS p.Leu74Pro

c.221T>C · rs200889086 · VCV1513347

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8897	likely pathogenic
REVEL	0.448	indeterminate
SaProt	LLR -13.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 687 bp · p 0.55 · regional, not allelic
Overall
CADD	27.4	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 0.000424% European (non-Finnish) · 5/1,179,990 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,460,768 alleles · very rare

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.Leu74Pro
Coding: c.221T>C
MANE Select: NM_001395517 · reported on NM_024664
dbSNP: rs200889086
Type: single nucleotide variant
Location: chr1:42456786 (GRCh38)

Full PPCS 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

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-leu74pro (accessed [today's date]).

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