Is NPHP4 p.Glu989Lys (c.2965G>A) pathogenic?

NPHP4 p.Glu989Lys (c.2965G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2025-12-30). AlphaMissense: ambiguous (0.3812); Rare (popmax 0.297%, mid); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Glu989Lys (c.2965G>A)?

NPHP4 p.Glu989Lys (c.2965G>A) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Glu989Lys (c.2965G>A) in the general population?

NPHP4 p.Glu989Lys (c.2965G>A) is rare (popmax 0.297%, mid) (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.Glu989Lys (c.2965G>A)?

AlphaMissense predicts ambiguous (score 0.3812) — an in-silico prediction, not a clinical call.

NPHP4 p.Glu989Lys

c.2965G>A · rs116606479 · VCV195608

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.3812 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.297%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
AlphaMissense	0.3812	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -12.49	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.1	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 0.297% Middle Eastern · 18/6,062 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.0294% 475/1,613,458 alleles · rare exomes 381/1,461,218 · genomes 94/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.297%	337
African / African-American	0.18%	556
South Asian	0.0758%	1,320
Remaining individualsnot grpmax-eligible	0.048%	2,083
Admixed American	0.0467%	2,143
European (non-Finnish)	0.0163%	6,145
East Asian	0.00446%	22,433
Finnishnot grpmax-eligible	0.00157%	63,550

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.Glu989Lys
Coding: c.2965G>A
MANE Select: NM_015102
dbSNP: rs116606479
Type: single nucleotide variant
Location: chr1:5874953 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 989: 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 focal segmental glomerulosclerosis

For Senior-Loken syndrome (Orphanet):

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

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-glu989lys (accessed [today's date]).

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