Is NPHP4 p.Pro1157Leu (c.3470C>T) pathogenic?

NPHP4 p.Pro1157Leu (c.3470C>T) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely benign (0.098); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Pro1157Leu (c.3470C>T)?

NPHP4 p.Pro1157Leu (c.3470C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Pro1157Leu (c.3470C>T) in the general population?

NPHP4 p.Pro1157Leu (c.3470C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about NPHP4 p.Pro1157Leu (c.3470C>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro1157Leu

c.3470C>T · rs1557592757 · VCV2316753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.605	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.48	donor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.39	loss · gain 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 0.87, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.7	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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000311% 5/1,609,338 alleles · very rare exomes 4/1,457,156 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
European (non-Finnish)	0.000254%	393,267

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: NPHP4
Protein: p.Pro1157Leu
Coding: c.3470C>T
MANE Select: NM_015102
dbSNP: rs1557592757
Type: single nucleotide variant
Location: chr1:5867742 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1157: the 'sufficient for basal bodies localization' region

Full NPHP4 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

NPHP4 p.Ala1220Val Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala1263Gly Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala649Asp Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala678Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala956Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala988Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1109Gln Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1135Cys 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/nphp4-p-pro1157leu (accessed [today's date]).

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