Is PPCS p.Phe175Leu (c.525T>A) pathogenic?

PPCS p.Phe175Leu (c.525T>A) is classified Uncertain significance in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.8246); Very rare (popmax 0.00169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPCS p.Phe175Leu (c.525T>A)?

PPCS p.Phe175Leu (c.525T>A) is associated with Inborn genetic diseases (ClinVar).

How common is PPCS p.Phe175Leu (c.525T>A) in the general population?

PPCS p.Phe175Leu (c.525T>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about PPCS p.Phe175Leu (c.525T>A)?

AlphaMissense predicts likely pathogenic (score 0.8246) — an in-silico prediction, not a clinical call.

PPCS p.Phe175Leu

c.525T>A · VCV4628240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ 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	0.8246	likely pathogenic
REVEL	0.134	moderately benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	GERP 0.81, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 2,669 bp · p 5.9e-05 · regional, not allelic
Overall
CADD	21.1	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 0.00169% European (non-Finnish) · 20/1,180,034 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,614,016 alleles · very rare exomes 19/1,461,884 · genomes 1/152,132 · 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.Phe175Leu
Coding: c.525T>A
MANE Select: NM_024664
Type: single nucleotide variant
Location: chr1:42457263 (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-phe175leu (accessed [today's date]).

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