Is NPHP1 c.771+2C>T pathogenic?

NPHP1 c.771+2C>T is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1093); Ultra-rare (popmax 0.0633%, amr); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 c.771+2C>T?

NPHP1 c.771+2C>T is associated with Inborn genetic diseases, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 c.771+2C>T in the general population?

NPHP1 c.771+2C>T is ultra-rare (popmax 0.0633%, amr) (gnomAD).

What do computational predictors say about NPHP1 c.771+2C>T?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

NPHP1 c.771+2C>T

rs189320299 · VCV92720

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0633%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
REVEL	0.113	moderately benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.94	donor gain · deltas
Constraint at this position
Conservation	phyloP 9.1	GERP -0.053, phastCons 1
Non-coding constraint	Z 0.26	1 kb window · o/e 0.98 · regional · uncalibrated
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals. Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0633% Admixed American · 38/60,010 alleles

Filtering AF 0.0474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0418%

Overall 0.00836% 135/1,613,988 alleles · ultra-rare exomes 103/1,461,842 · genomes 32/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0633%	1,579
Remaining individualsnot grpmax-eligible	0.0256%	3,907
European (non-Finnish)	0.00636%	15,733
African / African-American	0.00533%	18,750
East Asian	0.00446%	22,433

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: NPHP1
Coding: c.771+2C>T
MANE Select: NM_001128178
dbSNP: rs189320299
Type: single nucleotide variant
Location: chr2:110164686 (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

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

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect nephronophthisis inherited retinal dystrophy

Similar variants

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
NPHP1 c.522+1G>A 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-c-771-plus-2c-t (accessed [today's date]).

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