Is NPHP4 p.Arg344Cys (c.1030C>T) pathogenic?

NPHP4 p.Arg344Cys (c.1030C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-28). AlphaMissense: likely benign (0.0964); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg344Cys (c.1030C>T)?

NPHP4 p.Arg344Cys (c.1030C>T) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg344Cys (c.1030C>T) in the general population?

NPHP4 p.Arg344Cys (c.1030C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about NPHP4 p.Arg344Cys (c.1030C>T)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg344Cys

c.1030C>T · rs777428281 · VCV500412

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	26.3	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 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00136% 22/1,613,732 alleles · very rare exomes 20/1,461,606 · genomes 2/152,126 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,232
East Asian	0.00223%	44,878
African / African-American	0.00134%	74,878
European (non-Finnish)	0.0011%	90,756
South Asian	0.0011%	91,072

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.Arg344Cys
Coding: c.1030C>T
MANE Select: NM_015102
dbSNP: rs777428281
Type: single nucleotide variant
Location: chr1:5947193 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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.Arg344Leu Uncertain significance ★ ⚠ same residue
NPHP4 p.Arg344= Likely benign ★ same residue
NPHP4 p.Arg344His Uncertain significance ★ ⚠ 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

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-arg344cys (accessed [today's date]).

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