Is NPHP1 p.Leu63Phe (c.187C>T) pathogenic?

NPHP1 p.Leu63Phe (c.187C>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4154); Very rare (popmax 0.00231%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP1 p.Leu63Phe (c.187C>T)?

NPHP1 p.Leu63Phe (c.187C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP1 p.Leu63Phe (c.187C>T) in the general population?

NPHP1 p.Leu63Phe (c.187C>T) is very rare (popmax 0.00231%, eas) (gnomAD).

What do computational predictors say about NPHP1 p.Leu63Phe (c.187C>T)?

AlphaMissense predicts ambiguous (score 0.4154) — an in-silico prediction, not a clinical call.

NPHP1 p.Leu63Phe

c.187C>T · VCV3921380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4154	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -9.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.23	donor loss, 17 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	28.3	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 0.00231% East Asian · 1/43,382 alleles

Filtering AF 8.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.3e-05%

Overall 0.000293% 4/1,365,268 alleles · very rare exomes 4/1,213,072 · genomes 0/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00231%	43,382
European (non-Finnish)	0.000313%	319,538

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.Leu63Phe
Coding: c.187C>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110179641 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 63: 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.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
NPHP1 p.Asn59His Uncertain significance ★★ ⚠ same condition
NPHP1 p.Asp569Val 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-leu63phe (accessed [today's date]).

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