Is NPHP4 p.Pro831Leu (c.2492C>T) pathogenic?

NPHP4 p.Pro831Leu (c.2492C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0538); Ultra-rare (popmax 0.029%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Pro831Leu (c.2492C>T)?

NPHP4 p.Pro831Leu (c.2492C>T) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Pro831Leu (c.2492C>T) in the general population?

NPHP4 p.Pro831Leu (c.2492C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about NPHP4 p.Pro831Leu (c.2492C>T)?

AlphaMissense predicts likely benign (score 0.0538) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro831Leu

c.2492C>T · rs568060648 · VCV1411774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0538 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0538	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.8
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	0.007	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 0.029% East Asian · 13/44,848 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00347% 56/1,613,366 alleles · ultra-rare exomes 51/1,461,086 · genomes 5/152,280 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,450
South Asian	0.0286%	3,496
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0032%	31,234
African / African-American	0.00133%	75,034
European (non-Finnish)	0.0011%	90,739

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.Pro831Leu
Coding: c.2492C>T
MANE Select: NM_015102
dbSNP: rs568060648
Type: single nucleotide variant
Location: chr1:5880233 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 831: 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

Also linked: nephronophthisis

Similar variants

NPHP4 p.Pro831= Likely benign ★★ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C 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/nphp4-p-pro831leu (accessed [today's date]).

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