Is NPHP4 p.Ser905Asn (c.2714G>A) pathogenic?

NPHP4 p.Ser905Asn (c.2714G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-16). AlphaMissense: likely benign (0.0921); Rare (popmax 0.102%, afr); Associated with NPHP4-related disorder.

What condition is associated with NPHP4 p.Ser905Asn (c.2714G>A)?

NPHP4 p.Ser905Asn (c.2714G>A) is associated with NPHP4-related disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Ser905Asn (c.2714G>A) in the general population?

NPHP4 p.Ser905Asn (c.2714G>A) is rare (popmax 0.102%, afr) (gnomAD).

What do computational predictors say about NPHP4 p.Ser905Asn (c.2714G>A)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

NPHP4 p.Ser905Asn

c.2714G>A · rs368298952 · VCV594942

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NPHP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -3.3
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	1.68	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 0.102% African / African-American · 76/74,800 alleles

Filtering AF 0.0831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0764%

Overall 0.00536% 86/1,605,016 alleles · rare exomes 42/1,452,736 · genomes 44/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.102%	984
Admixed American	0.00676%	14,783
Remaining individualsnot grpmax-eligible	0.00645%	15,511
South Asian	0.00112%	89,612
European (non-Finnish)	8.51e-05%	1,175,391

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.Ser905Asn
Coding: c.2714G>A
MANE Select: NM_015102
dbSNP: rs368298952
Type: single nucleotide variant
Location: chr1:5877196 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 905: 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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

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
NPHP4 c.992+2T>C 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-ser905asn (accessed [today's date]).

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