Is NPEPPS p.Phe255Ser (c.764T>C) pathogenic?

NPEPPS p.Phe255Ser (c.764T>C) is classified Uncertain significance in NPEPPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-11). AlphaMissense: likely pathogenic (0.6865); Absent from gnomAD v4.1.

How common is NPEPPS p.Phe255Ser (c.764T>C) in the general population?

NPEPPS p.Phe255Ser (c.764T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPEPPS p.Phe255Ser (c.764T>C)?

AlphaMissense predicts likely pathogenic (score 0.6865) — an in-silico prediction, not a clinical call.

NPEPPS p.Phe255Ser

c.764T>C · VCV3921354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6865 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6865	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 61 kb · p 1.5e-59 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPEPPS
Protein: p.Phe255Ser
Coding: c.764T>C
MANE Select: NM_006310
Type: single nucleotide variant
Location: chr17:47585615 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.53 · 3 PDB
Residue 255: a β-strand

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-phe255ser (accessed [today's date]).

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