Is PPCS p.Arg133Trp (c.397A>T) pathogenic?

PPCS p.Arg133Trp (c.397A>T) is classified Conflicting classifications of pathogenicity in PPCS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0909); Ultra-rare (popmax 0.0743%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPCS p.Arg133Trp (c.397A>T)?

PPCS p.Arg133Trp (c.397A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPCS p.Arg133Trp (c.397A>T) in the general population?

PPCS p.Arg133Trp (c.397A>T) is ultra-rare (popmax 0.0743%, nfe) (gnomAD).

What do computational predictors say about PPCS p.Arg133Trp (c.397A>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

PPCS p.Arg133Trp

c.397A>T · rs199807362 · VCV1512518

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0743%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -11.75	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.9	GERP -0.8, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 687 bp · p 0.55 · regional, not allelic
Overall
CADD	22.0	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 0.0743% European (non-Finnish) · 877/1,179,962 alleles

Filtering AF 0.0702% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0685%

Overall 0.0603% 967/1,604,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0743%	1,345
Remaining individualsnot grpmax-eligible	0.0705%	1,419
Admixed American	0.045%	2,223
Finnishnot grpmax-eligible	0.0167%	6,001
South Asian	0.00659%	15,181
African / African-American	0.00533%	18,762

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.Arg133Trp
Coding: c.397A>T
MANE Select: NM_001395517 · reported on NM_024664
dbSNP: rs199807362
Type: single nucleotide variant
Location: chr1:42456962 (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-arg133trp (accessed [today's date]).

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