Is NPEPPS p.Pro552Ser (c.1654C>T) pathogenic?

NPEPPS p.Pro552Ser (c.1654C>T) is classified Uncertain significance in NPEPPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.2951); Very rare (popmax 0.00268%, afr).

How common is NPEPPS p.Pro552Ser (c.1654C>T) in the general population?

NPEPPS p.Pro552Ser (c.1654C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about NPEPPS p.Pro552Ser (c.1654C>T)?

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

NPEPPS p.Pro552Ser

c.1654C>T · VCV4558901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2951	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.35, phastCons 0.98
Regional constraint	o/e 0.69	unconstrained · MANE · 29 kb · p 2.4e-13 · regional, not allelic
Overall
CADD	21.0	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 0.00268% African / African-American · 2/74,688 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,611,944 alleles · very rare exomes 1/1,459,962 · genomes 1/151,982 · 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: NPEPPS
Protein: p.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_006310
Type: single nucleotide variant
Location: chr17:47601661 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.53 · 3 PDB

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

Similar variants

NPEPPS p.Ala330= Benign ★★ same type
NPEPPS p.Asp73= Likely benign ★★ same type
NPEPPS p.Gln357= Benign ★★ same type
NPEPPS p.Leu40= Benign ★★ same type
NPEPPS p.Ala236Ser Uncertain significance ★ ⚠ same type
NPEPPS p.Ala275Val Uncertain significance ★ ⚠ same type
NPEPPS p.Ala315Thr Uncertain significance ★ ⚠ same type
NPEPPS p.Ala555Gly Uncertain significance ★ ⚠ 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/npepps-p-pro552ser (accessed [today's date]).

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