Is CSTPP1 p.Pro218Ser (c.652C>T) pathogenic?

CSTPP1 p.Pro218Ser (c.652C>T) is classified Uncertain significance in CSTPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.9572); Ultra-rare (popmax 0.0191%, nfe).

How common is CSTPP1 p.Pro218Ser (c.652C>T) in the general population?

CSTPP1 p.Pro218Ser (c.652C>T) is ultra-rare (popmax 0.0191%, nfe) (gnomAD).

What do computational predictors say about CSTPP1 p.Pro218Ser (c.652C>T)?

AlphaMissense predicts likely pathogenic (score 0.9572) — an in-silico prediction, not a clinical call.

CSTPP1 p.Pro218Ser

c.652C>T · VCV4828623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9572	likely pathogenic · top 8% in CSTPP1
REVEL	0.411	indeterminate
SaProt	LLR -14.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 225 kb · p 0.76 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0191% European (non-Finnish) · 225/1,179,878 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0147% 238/1,613,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0191%	5,244
Finnishnot grpmax-eligible	0.0125%	8,002
Remaining individualsnot grpmax-eligible	0.0064%	15,625
African / African-American	0.00133%	74,990

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: CSTPP1
Protein: p.Pro218Ser
Coding: c.652C>T
MANE Select: NM_024113
Type: single nucleotide variant
Location: chr11:47157817 (GRCh38)
Structure: AlphaFold pLDDT 81.05
Residue 218: the 'required for interaction with tpgs1, lrrc49, and ttll1' region; the 'required for interaction with tpgs2' region

Full CSTPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSTPP1 p.Arg18Gln Uncertain significance ★ ⚠ same type
CSTPP1 p.Asn92Lys Uncertain significance ★ ⚠ same type
CSTPP1 p.Asp260His Uncertain significance ★ ⚠ same type
CSTPP1 p.Glu328Lys Uncertain significance ★ ⚠ same type
CSTPP1 p.Ser313Leu Uncertain significance ★ same type
CSTPP1 p.Asp327= 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/cstpp1-p-pro218ser (accessed [today's date]).

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