Is NPHP4 p.Arg1247Cys (c.3739C>T) pathogenic?

NPHP4 p.Arg1247Cys (c.3739C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-17). AlphaMissense: likely benign (0.1188); Ultra-rare (popmax 0.0173%, afr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Arg1247Cys (c.3739C>T)?

NPHP4 p.Arg1247Cys (c.3739C>T) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg1247Cys (c.3739C>T) in the general population?

NPHP4 p.Arg1247Cys (c.3739C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

How is Senior-Loken syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP4 p.Arg1247Cys (c.3739C>T)?

AlphaMissense predicts likely benign (score 0.1188) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg1247Cys

c.3739C>T · rs377686745 · VCV1026648

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1188	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.4	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 0.0173% African / African-American · 13/74,940 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00192% 31/1,612,828 alleles · ultra-rare exomes 24/1,460,586 · genomes 7/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,765
Middle Eastern	0.0165%	6,074
South Asian	0.00659%	15,176
East Asian	0.00446%	22,441
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
Remaining individualsnot grpmax-eligible	0.0032%	31,219
Admixed American	0.00167%	59,976
European (non-Finnish)	0.000424%	235,907

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.Arg1247Cys
Coding: c.3739C>T
MANE Select: NM_015102
dbSNP: rs377686745
Type: single nucleotide variant
Location: chr1:5865179 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1247: the 'sufficient for basal bodies localization' region

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

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Arg1247His Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg1247= Likely benign ★★ same residue
NPHP4 p.Arg1247fs Likely pathogenic ★ 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-arg1247cys (accessed [today's date]).

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