Is NPHP4 p.Arg1044Cys (c.3130C>T) pathogenic?

NPHP4 p.Arg1044Cys (c.3130C>T) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-08). AlphaMissense: likely benign (0.0872); Very rare (popmax 0.00416%, nfe).

How common is NPHP4 p.Arg1044Cys (c.3130C>T) in the general population?

NPHP4 p.Arg1044Cys (c.3130C>T) is very rare (popmax 0.00416%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Arg1044Cys (c.3130C>T)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg1044Cys

c.3130C>T · VCV3350314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00416%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.8, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	21.7	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 0.00416% European (non-Finnish) · 49/1,178,086 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00348% 56/1,608,676 alleles · very rare exomes 55/1,456,474 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00416%	24,043
Admixed American	0.00337%	29,712
South Asian	0.00223%	44,854
Remaining individualsnot grpmax-eligible	0.00161%	62,286
Finnishnot grpmax-eligible	0.00158%	63,316
African / African-American	0.00134%	74,798

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.Arg1044Cys
Coding: c.3130C>T
MANE Select: NM_015102
Type: single nucleotide variant
Location: chr1:5874572 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1044: the 'sufficient for basal bodies localization' region; a UniProt-annotated variant site (found in a patient with cardiac laterality defects; fails to rescue heart looping defects in zebrafish knockout)

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NPHP4 p.Arg1044His Uncertain significance ★★ ⚠ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same type
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.2611+1G>C Pathogenic ★★ same type
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP4 c.518-2A>G Likely pathogenic ★★ same type

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-arg1044cys (accessed [today's date]).

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