Is NPHP3 p.Ser1053Phe (c.3158C>T) pathogenic?

NPHP3 p.Ser1053Phe (c.3158C>T) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: ambiguous (0.419); Very rare (popmax 0.00139%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Ser1053Phe (c.3158C>T)?

NPHP3 p.Ser1053Phe (c.3158C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP3 p.Ser1053Phe (c.3158C>T) in the general population?

NPHP3 p.Ser1053Phe (c.3158C>T) is very rare (popmax 0.00139%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Ser1053Phe (c.3158C>T)?

AlphaMissense predicts ambiguous (score 0.419) — an in-silico prediction, not a clinical call.

NPHP3 p.Ser1053Phe

c.3158C>T · rs1213673024 · VCV3201648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.419	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -12.93	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.7	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

Grpmax group 0.00139% African / African-American · 1/71,792 alleles

Overall 6.84e-05% 1/1,462,306 alleles · very rare exomes 0/1,310,490 · genomes 1/151,816 · 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: NPHP3
Protein: p.Ser1053Phe
Coding: c.3158C>T
MANE Select: NM_153240
dbSNP: rs1213673024
Type: single nucleotide variant
Location: chr3:132687194 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 p.Ser1053fs Pathogenic/Likely pathogenic ★★ same residue
NPHP3 p.Ala1203Val Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg605Cys Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg705His Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg756Trp Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn1097Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn218Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn776Ser Uncertain significance ★★ ⚠ same condition

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/nphp3-p-ser1053phe (accessed [today's date]).

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