Is NPHP1 p.Thr368Ile (c.1103C>T) pathogenic?

NPHP1 p.Thr368Ile (c.1103C>T) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-06). AlphaMissense: likely benign (0.298); Very rare (popmax 0.00329%, sas); Associated with Senior-Loken syndrome 1.

What condition is associated with NPHP1 p.Thr368Ile (c.1103C>T)?

NPHP1 p.Thr368Ile (c.1103C>T) is associated with Senior-Loken syndrome 1, nephronophthisis 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Thr368Ile (c.1103C>T) in the general population?

NPHP1 p.Thr368Ile (c.1103C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Senior-Loken syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP1 p.Thr368Ile (c.1103C>T)?

AlphaMissense predicts likely benign (score 0.298) — an in-silico prediction, not a clinical call.

NPHP1 p.Thr368Ile

c.1103C>T · rs778528184 · VCV1385945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Senior-Loken syndrome 1

Computational evidence

Protein change
AlphaMissense	0.298	likely benign
REVEL	0.654	pathogenic-leaning
SaProt	LLR -10.91	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6.4	GERP 0.68, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T423I vs ClinVar T368I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000434% 7/1,613,930 alleles · very rare exomes 7/1,461,628 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.00017%	589,915

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.Thr368Ile
Coding: c.1103C>T
MANE Select: NM_001128178
dbSNP: rs778528184
Type: single nucleotide variant
Location: chr2:110150237 (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

Senior-Loken syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Joubert syndrome with renal defect nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

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-p-thr368ile (accessed [today's date]).

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