Is PPCS p.Ala8Ser (c.22G>T) pathogenic?

PPCS p.Ala8Ser (c.22G>T) is classified Uncertain significance in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-09). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.000178%, nfe).

How common is PPCS p.Ala8Ser (c.22G>T) in the general population?

PPCS p.Ala8Ser (c.22G>T) is very rare (popmax 0.000178%, nfe) (gnomAD).

What do computational predictors say about PPCS p.Ala8Ser (c.22G>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

PPCS p.Ala8Ser

c.22G>T · rs777660196 · VCV2095754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.64	GERP -4.8
Regional constraint	o/e 1.04	unconstrained · MANE · 687 bp · p 0.55 · regional, not allelic
Overall
CADD	7.257	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000178% European (non-Finnish) · 2/1,125,786 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000149% 2/1,345,786 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.Ala8Ser
Coding: c.22G>T
MANE Select: NM_024664
dbSNP: rs777660196
Type: single nucleotide variant
Location: chr1:42456587 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.94 · 2 PDB

Full PPCS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPCS p.Ala162Pro Uncertain significance ★★ ⚠ same type
PPCS p.Pro107Ser Uncertain significance ★★ ⚠ same type
PPCS c.*91T>G Benign ★★ same type
PPCS p.Leu280= Benign/Likely benign ★★ same type
PPCS p.Phe73= Likely benign ★★ same type
PPCS p.Leu118Met Uncertain significance ★ ⚠ same type
PPCS p.Thr68Pro Uncertain significance ★ ⚠ same type
PPCS c.508+14G>C Likely benign ★ same type

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-ala8ser (accessed [today's date]).

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