Is NPHP1 p.Ala159Ser (c.475G>T) pathogenic?

NPHP1 p.Ala159Ser (c.475G>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-26). AlphaMissense: likely benign (0.2348); Very rare (popmax 0.00223%, eas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Ala159Ser (c.475G>T)?

NPHP1 p.Ala159Ser (c.475G>T) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Ala159Ser (c.475G>T) in the general population?

NPHP1 p.Ala159Ser (c.475G>T) is very rare (popmax 0.00223%, 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.Ala159Ser (c.475G>T)?

AlphaMissense predicts likely benign (score 0.2348) — an in-silico prediction, not a clinical call.

NPHP1 p.Ala159Ser

c.475G>T · rs372855293 · VCV1006754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.2348	likely benign
REVEL	0.556	indeterminate
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.77, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	18.78	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,846 alleles

Overall 0.000124% 2/1,613,596 alleles · very rare exomes 1/1,461,578 · genomes 1/152,018 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,846
European (non-Finnish)	8.48e-05%	1,179,782

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.Ala159Ser
Coding: c.475G>T
MANE Select: NM_001128178
dbSNP: rs372855293
Type: single nucleotide variant
Location: chr2:110169853 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 159: the sh3 domain; a β-strand

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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 p.Ala159= Likely benign ★★ same residue
NPHP1 p.Ala159Thr Uncertain significance ★ ⚠ same residue
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-ala159ser (accessed [today's date]).

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