Is NPHP4 p.Asp1193Glu (c.3579C>G) pathogenic?

NPHP4 p.Asp1193Glu (c.3579C>G) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.7072); Very rare (popmax 0.00179%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Asp1193Glu (c.3579C>G)?

NPHP4 p.Asp1193Glu (c.3579C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Asp1193Glu (c.3579C>G) in the general population?

NPHP4 p.Asp1193Glu (c.3579C>G) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Asp1193Glu (c.3579C>G)?

AlphaMissense predicts likely pathogenic (score 0.7072) — an in-silico prediction, not a clinical call.

NPHP4 p.Asp1193Glu

c.3579C>G · VCV4122109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7072	likely pathogenic
REVEL	0.408	indeterminate
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.4	GERP -4.1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	1.11	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 0.00179% European (non-Finnish) · 21/1,174,480 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000975%

Overall 0.00131% 21/1,603,850 alleles · very rare exomes 21/1,451,582 · genomes 0/152,268 · joint denominator

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.Asp1193Glu
Coding: c.3579C>G
MANE Select: NM_015102
Type: single nucleotide variant
Location: chr1:5866438 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1193: the 'sufficient for basal bodies localization' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP4 p.Ala1220Val Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala1263Gly Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala649Asp Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala678Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala956Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala988Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1109Gln Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1135Cys Uncertain significance ★★ ⚠ 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-asp1193glu (accessed [today's date]).

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