Is NPHP4 p.Gln569Glu (c.1705C>G) pathogenic?

NPHP4 p.Gln569Glu (c.1705C>G) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0837); Low-frequency (popmax 1.4%, afr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Gln569Glu (c.1705C>G)?

NPHP4 p.Gln569Glu (c.1705C>G) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Gln569Glu (c.1705C>G) in the general population?

NPHP4 p.Gln569Glu (c.1705C>G) is low-frequency (popmax 1.4%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP4 p.Gln569Glu (c.1705C>G)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

NPHP4 p.Gln569Glu

c.1705C>G · rs113413307 · VCV235419

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.4%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	23.0	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 1.4% African / African-American · 1,050/75,060 alleles

Filtering AF 1.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3%

Overall 0.0775% 1,251/1,613,932 alleles · low-frequency exomes 618/1,461,566 · genomes 633/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.4%	71
Remaining individualsnot grpmax-eligible	0.182%	548
Admixed American	0.1%	1,000
Middle Eastern	0.0825%	1,212
South Asian	0.0132%	7,587
European (non-Finnish)	0.000848%	117,985

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.Gln569Glu
Coding: c.1705C>G
MANE Select: NM_015102
dbSNP: rs113413307
Type: single nucleotide variant
Location: chr1:5905690 (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

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 p.Gln569Ter Pathogenic ★ same residue
NPHP4 p.Gln569fs 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
NPHP4 c.517+1G>A 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-gln569glu (accessed [today's date]).

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