Is NPHP1 p.Arg15Cys (c.43C>T) pathogenic?

NPHP1 p.Arg15Cys (c.43C>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: ambiguous (0.4237); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Arg15Cys (c.43C>T)?

NPHP1 p.Arg15Cys (c.43C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Arg15Cys (c.43C>T) in the general population?

NPHP1 p.Arg15Cys (c.43C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about NPHP1 p.Arg15Cys (c.43C>T)?

AlphaMissense predicts ambiguous (score 0.4237) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg15Cys

c.43C>T · rs373915635 · VCV3201642

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4237	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	33.0	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 0.00667% African / African-American · 5/74,932 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,613,902 alleles · very rare exomes 3/1,461,704 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
Admixed American	0.00333%	30,006

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.Arg15Cys
Coding: c.43C>T
MANE Select: NM_001128178
dbSNP: rs373915635
Type: single nucleotide variant
Location: chr2:110204926 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 15: an α-helix

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

Similar variants

NPHP1 p.Arg15Leu Uncertain significance ★★ ⚠ same residue
NPHP1 p.Arg15Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
NPHP1 p.Gly287Arg Pathogenic ★★ same condition
NPHP1 c.771+136C>A Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+26A>G Uncertain significance ★★ ⚠ same condition
NPHP1 c.771+38G>T Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg389His Uncertain significance ★★ ⚠ same condition
NPHP1 p.Arg628Gln Uncertain significance ★★ ⚠ 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-arg15cys (accessed [today's date]).

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