Is NPHP1 p.Ile271Phe (c.811A>T) pathogenic?

NPHP1 p.Ile271Phe (c.811A>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: ambiguous (0.447); Absent from gnomAD v4.1; Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Ile271Phe (c.811A>T)?

NPHP1 p.Ile271Phe (c.811A>T) is associated with nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Ile271Phe (c.811A>T) in the general population?

NPHP1 p.Ile271Phe (c.811A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPHP1 p.Ile271Phe (c.811A>T)?

AlphaMissense predicts ambiguous (score 0.447) — an in-silico prediction, not a clinical call.

NPHP1 p.Ile271Phe

c.811A>T · VCV3584260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.447 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

nephronophthisis 1

Computational evidence

Protein change
AlphaMissense	0.447	ambiguous
REVEL	0.502	indeterminate
SaProt	LLR -7.90	tolerated
Splicing
SpliceAI	Δ0.22	donor loss, 48 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.64	GERP 1.7, phastCons 0.45
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I326F vs ClinVar I271F) — verify the residue.

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: NPHP1
Protein: p.Ile271Phe
Coding: c.811A>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110163096 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 1 Joubert syndrome with renal defect

Similar variants

NPHP1 p.Ile271Val Uncertain significance ★★ ⚠ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ 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/nphp1-p-ile271phe (accessed [today's date]).

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