Is PPCS p.Arg25Pro (c.74G>C) pathogenic?

PPCS p.Arg25Pro (c.74G>C) is classified Likely benign in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-27). AlphaMissense: likely benign (0.2951); Rare (popmax 0.937%, eas).

How common is PPCS p.Arg25Pro (c.74G>C) in the general population?

PPCS p.Arg25Pro (c.74G>C) is rare (popmax 0.937%, eas) (gnomAD).

What do computational predictors say about PPCS p.Arg25Pro (c.74G>C)?

AlphaMissense predicts likely benign (score 0.2951) — an in-silico prediction, not a clinical call.

PPCS p.Arg25Pro

c.74G>C · rs774666574 · VCV4820387

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2951 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.937%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2951	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -10.69	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 4.4	GERP 1.2, phastCons 0.94
Regional constraint	o/e 1.04	unconstrained · MANE · 687 bp · p 0.55 · regional, not allelic
Overall
CADD	21.5	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 0.937% East Asian · 391/41,722 alleles

Filtering AF 0.861% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.83%

Overall 0.194% 2,695/1,389,424 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.937%	107
Admixed American	0.899%	111
Finnishnot grpmax-eligible	0.424%	236
South Asian	0.327%	306
African / African-American	0.234%	427
Remaining individualsnot grpmax-eligible	0.13%	769
European (non-Finnish)	0.0956%	1,046
Ashkenazi Jewishnot grpmax-eligible	0.0727%	1,375
Middle Eastern	0.0179%	5,586

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.Arg25Pro
Coding: c.74G>C
MANE Select: NM_001395517 · reported on NM_024664
dbSNP: rs774666574
Type: single nucleotide variant
Location: chr1:42456639 (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-arg25pro (accessed [today's date]).

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