Is NPHP1 p.Tyr206Phe (c.617A>T) pathogenic?

NPHP1 p.Tyr206Phe (c.617A>T) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1272); Ultra-rare (popmax 0.0246%, eas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Tyr206Phe (c.617A>T)?

NPHP1 p.Tyr206Phe (c.617A>T) is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Tyr206Phe (c.617A>T) in the general population?

NPHP1 p.Tyr206Phe (c.617A>T) is ultra-rare (popmax 0.0246%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP1 p.Tyr206Phe (c.617A>T)?

AlphaMissense predicts likely benign (score 0.1272) — an in-silico prediction, not a clinical call.

NPHP1 p.Tyr206Phe

c.617A>T · VCV3584272

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1272 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1272	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0246% East Asian · 11/44,796 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000934% 15/1,606,532 alleles · ultra-rare exomes 13/1,454,430 · genomes 2/152,102 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0246%	4,072
European (non-Finnish)	0.000341%	293,317

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.Tyr206Phe
Coding: c.617A>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110168459 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 206: the sh3 domain; the 'disordered' region

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

Disease context

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

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

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

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-tyr206phe (accessed [today's date]).

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