Is NPHP4 p.Asp709Val (c.2126A>T) pathogenic?

NPHP4 p.Asp709Val (c.2126A>T) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely benign (0.1629); Very rare (popmax 0.0022%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Asp709Val (c.2126A>T)?

NPHP4 p.Asp709Val (c.2126A>T) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Asp709Val (c.2126A>T) in the general population?

NPHP4 p.Asp709Val (c.2126A>T) is very rare (popmax 0.0022%, sas) (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.Asp709Val (c.2126A>T)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

NPHP4 p.Asp709Val

c.2126A>T · rs926092150 · VCV1045837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.66, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	21.1	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 0.0022% South Asian · 2/90,740 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,610,626 alleles · very rare exomes 3/1,458,276 · genomes 0/152,350 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,370
European (non-Finnish)	8.49e-05%	1,177,432

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.Asp709Val
Coding: c.2126A>T
MANE Select: NM_015102
dbSNP: rs926092150
Type: single nucleotide variant
Location: chr1:5904634 (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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Asp709Ala Uncertain significance ★ ⚠ same residue
NPHP4 p.Asp709Asn Uncertain significance ★ ⚠ same residue
NPHP4 p.Asp709Gly 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

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-asp709val (accessed [today's date]).

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