Is NPHP1 p.Thr596Met (c.1787C>T) pathogenic?

NPHP1 p.Thr596Met (c.1787C>T) is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.0695); Ultra-rare (popmax 0.0408%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Thr596Met (c.1787C>T)?

NPHP1 p.Thr596Met (c.1787C>T) is associated with Inborn genetic diseases, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Thr596Met (c.1787C>T) in the general population?

NPHP1 p.Thr596Met (c.1787C>T) is ultra-rare (popmax 0.0408%, nfe) (gnomAD).

What do computational predictors say about NPHP1 p.Thr596Met (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

NPHP1 p.Thr596Met

c.1787C>T · rs201460699 · VCV288529

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0408%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.3	GERP -3.9
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	2.543	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 T651M vs ClinVar T596M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0408% European (non-Finnish) · 482/1,179,946 alleles

Filtering AF 0.0378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0312% 504/1,613,970 alleles · ultra-rare exomes 487/1,461,802 · genomes 17/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0408%	2,448
Remaining individualsnot grpmax-eligible	0.024%	4,166
Finnishnot grpmax-eligible	0.00781%	12,804
African / African-American	0.00267%	37,464

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
Protein: p.Thr596Met
Coding: c.1787C>T
MANE Select: NM_001128178
dbSNP: rs201460699
Type: single nucleotide variant
Location: chr2:110124038 (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

Similar variants

NPHP1 p.Thr596= Likely benign ★ same residue
NPHP1 p.Thr596Ala 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

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-thr596met (accessed [today's date]).

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