Is NPHP4 p.Arg674Leu (c.2021G>T) pathogenic?

NPHP4 p.Arg674Leu (c.2021G>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.5867); Rare (popmax 0.577%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Arg674Leu (c.2021G>T)?

NPHP4 p.Arg674Leu (c.2021G>T) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg674Leu (c.2021G>T) in the general population?

NPHP4 p.Arg674Leu (c.2021G>T) is rare (popmax 0.577%, 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.Arg674Leu (c.2021G>T)?

AlphaMissense predicts likely pathogenic (score 0.5867) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg674Leu

c.2021G>T · rs375416303 · VCV499988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5867 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.577%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.5867	likely pathogenic
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	28.2	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 0.577% South Asian · 526/91,084 alleles

Filtering AF 0.537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.52%

Overall 0.0355% 573/1,613,968 alleles · rare exomes 540/1,461,694 · genomes 33/152,274 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.577%	173
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.048%	2,083
African / African-American	0.0107%	9,378
Admixed American	0.00167%	60,018
European (non-Finnish)	0.000424%	235,976

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.Arg674Leu
Coding: c.2021G>T
MANE Select: NM_015102
dbSNP: rs375416303
Type: single nucleotide variant
Location: chr1:5904739 (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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Arg674Cys Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg674His 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

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-arg674leu (accessed [today's date]).

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