Is NPHP4 p.Ser908= (c.2724G>A) pathogenic?

NPHP4 p.Ser908= (c.2724G>A) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). Common (popmax 9.82%, afr) — too common for a highly-penetrant pathogenic allele; Associated with kidney disorder.

What condition is associated with NPHP4 p.Ser908= (c.2724G>A)?

NPHP4 p.Ser908= (c.2724G>A) is associated with kidney disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

NPHP4 p.Ser908=

Q: How common is NPHP4 p.Ser908= (c.2724G>A) in the general population?

NPHP4 p.Ser908= (c.2724G>A) is common (popmax 9.82%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2724G>A · rs114545322 · VCV95678

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 9.82%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

kidney disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.5	GERP -3.3
Overall
CADD	1.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.82% African / African-American · 7,347/74,850 alleles

Filtering AF 9.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.55%

Overall 0.541% 8,677/1,603,148 alleles · common exomes 4,431/1,450,782 · genomes 4,246/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.82%	10
Admixed American	0.672%	149
Remaining individualsnot grpmax-eligible	0.642%	156
Middle Eastern	0.382%	262
Ashkenazi Jewishnot grpmax-eligible	0.102%	978
European (non-Finnish)	0.0398%	2,515
South Asian	0.0168%	5,952
East Asian	0.00225%	44,400

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.Ser908=
Coding: c.2724G>A
MANE Select: NM_015102
dbSNP: rs114545322
Type: single nucleotide variant
Location: chr1:5877186 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 908: the 'sufficient for basal bodies localization' region; the 'disordered' region

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

Disease context

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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Ser908Leu 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
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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-ser908 (accessed [today's date]).

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