Is PPCS p.Ser281Ter (c.842C>A) pathogenic?

PPCS p.Ser281Ter (c.842C>A) is classified Uncertain significance in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Very rare (popmax 0.0011%, sas).

How common is PPCS p.Ser281Ter (c.842C>A) in the general population?

PPCS p.Ser281Ter (c.842C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

PPCS p.Ser281Ter

c.842C>A · rs755339358 · VCV1974946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Overall 6.2e-05% 1/1,614,040 alleles · very rare exomes 1/1,461,850 · genomes 0/152,190 · 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.Ser281Ter
Coding: c.842C>A
MANE Select: NM_024664
dbSNP: rs755339358
Type: single nucleotide variant
Location: chr1:42459832 (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-ser281ter (accessed [today's date]).

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